WO2011083150A2 - Obesity small molecules - Google Patents

Abstract

The present invention relates to new therapies to treat obesity and related diseases, as well as for reducing triglyceride levels and body weight.

Description

Obesity small molecules

The present invention relates to the field of pharmaceutical compounds and methods for the treatment of overweight and obe^¬ sity.

The world health organization currently estimates that as of 2009 over 1 billion individuals worldwide are overweight. Almost one third of these individuals are clinically obese, markedly raising their chances of cardiovascular disease, type-2 diabetes, cancer, and stroke. The regulation of body fat content in animals results from the integration of multiple nutrient, sen^¬ sory, and hormonal inputs primarily at the level of the brain and adipose tissues. This integrative network is influenced not only by genetics, but also by circadian rhythm and physical and social environments. Obesity is thus, a complex, systems level disease .

Spurned by the discovery of leptin, tremendous progress has been made in identifying the molecular players and pathways regulating adiposity. The impressive bounds made through the study of gene-targeted mice and the tracking of monogenic obe^¬ sity disorders in humans, have been complemented by studies in lower organisms. Virtually all key metabolic regulators examined to date display conserved functions across phyla, including for instance, insulin signaling, mTOR, and key lipases such as ATGL. Similar to mammals, model organisms such as Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans employ multiple molecular and tissue-based regulatory networks to bal^¬ ance energy needs, nutritional state, and aging and thus repre^¬ sent potent genomics tools for the study of metabolism. For in^¬ stance, an RNAi feeding model was used to identify potential regulators of fat storage in the C. elegans genome.

It is a goal of the present invention to identify further genes, enzymatic pathways and active compounds for their modula^¬ tion suitable for the treatment of triglyceride dysfunction, overweight and obesity.

The present invention therefore provides a method of reduc^¬ ing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1. E.g. a therapeutic dose disclosed or approved for other therapeutic uses for each of these compounds can be used. In a further aspect the present invention provides a method of reducing triglyceride levels, in particular LDL levels, in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.

In a related aspect the present invention provides the use of a compound of table 1 for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat obesity in a subject. Also provided are these compounds for use in the therapies discloed herein. The inven^¬ tion is further defined by the subject matter of the claims.

In particular the present invention relates to use of the following compounds for the above tratments, in particular for reducing weight and/or body fat in a subject:

• Vandetanib,

• Dasatinib,

• Tanespimycin ( 17-allylamino-demethoxygeldamycin, "17-AAG") ,

• S-17092,

• Sorafenib,

• Lintopride,

• Fenoprofen,

• Sulfaphenazole,

• Fluticasone (including Fluticasone propionate, "Ubizol") ,

• Rolipram,

• Febuxostat,

• Verapamil (including Norverapamil ) ,

• a therapeutic compound selected from a modulator of gene CG9438, or an ortholog thereof, in particular the human orthologue CYP3A4, the compounds being selected from er- lotinib, gefitinib and lapatinib,

• a therapeutic compound selected from a modulator of gene CG8222, or an ortholog thereof, in particular the human orthologue KDR, the compounds being selected from axitinib, pazopanib and semaxanib (also known as Semaxinib or SU 5416) ,

• a therapeutic compound selected from a modulator of gene CG6919, or an ortholog thereof, in particular the human orthologue HTR4, the compounds being selected from cis^¬ apride, mosapride, piboserod, prucalopride, renzapride, tegaserod, tropisetron and zacopride,

or any combination of the above compounds with any one or more compounds selected from the compounds of table 1, preferably with the compounds given above. However, in other embodiments the compounds may be used alone in the inventive treatment de^¬ scribed herein. According to this embodiment the invention pro^¬ vides for the inventive therapy wherein the compound is adminis^¬ tered as the only therapeutic compound active (or indicated) in a treatment of reducing weight and/or body fat or of obesity in a subject. In particular, the inventive compound, especially Lintopride, is used for administration without a DPP IV inhibi^¬ tor as disclosed in the WP 2006/005613

The inventive use of the compounds given herein includes the use of any pharmaceutically acceptable salt or hydrate form thereof .

In preferred embodiments the inventive compounds are used in the treatment of obesity, in particular severe obesity. Obesity is defined as an excess of body fat. Body mass index (BMI - the ratio of body weight in kg to the square of the height of an in^¬ dividual in m) , is a useful measure of fat distribution. Impor^¬ tantly it allows the stratification of patient categories to identify increased risk of morbidity and mortality and the iden^¬ tification of suitable interventions. Furthermore it provides a firm basis for the assessment of intervention strategies. The stratification of obesity using BMI is as follows. BMI ≥25 = Overweight, BMI 25-29.99 = Preobese, BMI 30-34.99 = Obese class I, BMI 35-39.99 = Obese class II, BMI > 40 = Obese class III (WHO 2000) . Class II obesity is severe obesity and class III obesity is referred to as extreme obesity, associated with an extremely high risk of comorbidities including Type 2 diabetes mellitus; Hypertension; Dyslipidemia; Cardiovascular disease including Coronary artery disease, Stroke and Congestive heart failure; Nonalcoholic fatty liver disease (steatosis, steato- hepatitis, cirrhosis) ; Respiratory disease including Obstructive sleep apnea, Obesity-hypoventilation syndrome, Asthma, Restric^¬ tive lung disease; Cancer; Osteoarthritis; Cholelithiasis; Gas^¬ troesophageal reflux disease; Gynecologic abnormalities includ^¬ ing Infertility, Abnormal menses; Venous stasis; Skin problems such as Intertrigo and Cellulitis; Increased risk of complica^¬ tions during surgery or pregnancy; Urinary incontinence; Idio^¬ pathic intracranial hypertension (Hensrud et al . , 2006) . As the degree of obesity increases so does the risk of all cause mor- tality. Extreme obesity has been estimated to lead to a shorten^¬ ing of life of between 5 and 20 years depending on other factors including sex, age and racial group (Fontaine et al . , 2003) .

Bariatric surgery is a common treatment for severely obese pa^¬ tients and the numbers of surgery performed per year is increas^¬ ing along with the increased prevalence of obesity and in par^¬ ticular severe obesity. The number of bariatric surgeries per^¬ formed in the US increased from 13,386 in 1998 to an estimated 170,000 in 2005 (Ecinosa et al . , 2005). However only 0.6% of over 11 million extremely obese patients in 2002 are eligible for surgery actually underwent a bariatric procedure (Ecinosa et al . , 2005) . Furthermore extreme obesity is also associated with an increased prevalence of psychiatric illnesses. Between a half and two-thirds of all bariatric surgery candidates possess an Axis I psychiatric disorder such as depression, somatization, social phobia, hypochondriasis, or obsessive-compulsive disorder (Rosick et al . , 2005; Sarwer et al . , 2004).

The subject to be treated according to the present invention can be any nun-human animal or a human. Preferably the subject is a mammal, in particular preferred embodiments a human.

According to the present invention obesity, diseases associ^¬ ated with obesity, e.g. diabetes, can be treated or prevented, in particular in the meaning of a prophylactic administration. "Preventing" or "prevention" herein does not require absolute success in the sense of an absolute prevention of a heart dis^¬ ease but indicates a reduced risk of developing a disease, or developing a disease with reduced severity. Likewise, "treat^¬ ment" shall not be construed as an absolute cure, but may also relate to amelioration of the disease or disease symptoms.

"About" is used to refer to certain dosages that can vary from a given value, nevertheless with the same effects as the indicated dose. In some embodiments "about" may refer to +/- 20% or 10% of a given value.

Preferably the compound is administered in a dosage suffi^¬ cient to treat or prevent said diseases. Administration can e.g. be a sinlge dose administration or a successive or repeated ad^¬ ministration, e.g. twice a day, daily or in an interval of at least 1 day, at least 2 days, at least 3 days, at least 1 week, preferably at least 2 weeks, at least 4 weeks, at least 8 weeks or even more preferred at least 12 weeks. According to a further preferred embodiment of the present invention, the compound is provided in a pharmaceutical composi^¬ tion or a medicament. The composition or medicament may comprise a pharmaceutical carrier. Pharmaceutical carrier substances serve for a better tolerance of the medicament and allow for a better solubility as well as a better bioavailability of the ac^¬ tive substances contained in the medicament. Examples of this are emulsifiers, thickening agents, redox components, starch, alcohol solutions, polyethylene glycol or lipids. The choice of a suitable pharmaceutical carrier is highly dependent on the manner of administration. For oral administrations, liquid or solid carriers may be used, for injections, liquid final compo^¬ sitions are required. For cellular targeting suitable vehicles can be includes such as liposomes or microsomes.

Preferably, the medicament or the compound to be used ac^¬ cording to the invention comprises buffer substances or tonic substances. By means of a buffer, the pH of the medicament can be adjusted to physiological conditions, and moreover, pH fluc^¬ tuations can be attenuated, or buffered, respectively. An exam^¬ ple thereof is a phosphate buffer. Tonic substances serve for adjusting the osmolarity and may comprise ionic substances, such as, e.g., inorganic salts, such as NaCl, or also non-ionic sub^¬ stances, such as, e.g. glycerol or carbohydrates.

The inventive compound or medicament can be administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or in- halational. Preferred routes of administration of the inventive agent according to the present invention are parenteral routes, preferably intraperitoneal or intravenous administration, intra^¬ venous administration being specifically preferred. Intravenous administration can be performed e.g. via bolus injection or by continuous intravenous delivery over a longer time period (e.g. 30 min to 6 h, especially 1 to 3 h) . Further routes include oral or transdermal or subcutaneous routes. In particular preferred is oral administration. For digestible agents, such as active proteins, peptides or siRNA, parenteral routes are preferred.

The medicament or the compound to be used according to the invention can be prepared to be suitable for oral or intranasal administration. These administration forms of the medicament of the present invention allow for a rapid an uncomplicated uptake of the active substances via the mucous membranes. For a nasal intake, nose drops or nose sprays are suitable. For an oral ad^¬ ministration, solid or liquid medicaments may, e.g., be taken directly or in a dissolved or diluted state, respectively.

The medicament or compound to be used according to the in^¬ vention can be prepared for an intravenous, intra-arterial , in^¬ tramuscular, intravascular, systemic, intraperitoneal or subcu^¬ taneous administration. For this purpose, e.g., injections or transfusions are suitable. Administrations directly into the bloodstream have the advantage that the active substances of the medicament will be distributed in the entire body and will quickly reach the target tissue, in particular the heart muscle.

The compound may be administered in a effective therapeutic dose. Effective doses are in the range of dosages known for these compounds for other, non-obesity related administrations. In particular, for a specific use a dosage can be determined by a simple test using drosophila or mouse test systems, e.g. as shown in example 3. Preferably the dosage is determined in a mouse test, e.g. using DIO B6 mice, at six weeks of age, mice are fed high fat diet to induce obesity, e.g. a 60 kcal% fat diet. The appropriate dosage can be correlated with reduced obe^¬ sity symptoms, in particular fat mass or body weight. Example dosages are at least 0.01 mg/kg, at least 0.1 mg/kg, at least 1 mg/kg, at least 10 mg/kg and/or up to 1 mg/kg, up to 10 mg/kg, up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Pre^¬ ferred dosage ranges are between 0.01 mg/kg and 1 g/kg, prefera^¬ bly between 0.1 mg/kg and 100 mg/kg.

Vandetanib

Vandetanib also known as Zactima; ZD6474; 4-Bromo-2-fluoro- phenyl) - [ 6-methoxy-7- ( 1 -methyl-piperidin-4-ylmethoxy) - quina- zolin-4-yl ] -amine is an orally available tyrosine kinase inhibi^¬ tor (TKI) .

Vandetanib is currently in clinical trials for the treatment of various cancers, including colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma and medullary thyroid cancer. Vandetanib is currently under review by the FDA Oncologic Drugs Advisory Committee (ODAC) proposed to be indicated for the treatment of patients with unresectable locally advanced or me- tastatic medullary thyroid cancer.

It may be administrered orally at doses ranging from 15mg to 300mg once daily. An oral dose of 300mg once daily is the maxi^¬ mum tolerated dose in humans. Doses used in the clinic range be^¬ tween lOOmg and 300mg.

Dasatinib

Dasatinib is also known as BMS-354825. Dasatinib is indi^¬ cated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib .

A recommended oral starting dose of dasatinib in chronic phase CML is 100 mg once daily. The recommended starting dose for accelerated, myeloid, or lymphoid blast phase CML or Phila^¬ delphia chromosome-positive ALL is 70 mg twice daily. Doses of up to 140 mg once daily have been used in patients with chronic phase CML, and up to 100 mg twice daily in those with advanced phase CML, or with ALL. It may also be administered 15 to 240 mg per day (60kg adult human dose), preferably orally.

Sorafenib

Sorafenib and the tosylate salt form Sorafenib Tosylate (chemical name 4- (4- { 3- [4-chloro-

3 ( trifluoromethyl ) phenyl ] ureido jphenoxy) -N2-methylpyridine-2- carboxamide-4-methylbenzenesulfonate) inhibits tumour cell pro^¬ liferation and angiogenesis by targeting RAF Kinases and VEGF Receptors. Sorafenib is generally prepared as its tosylate salt form. Sorafenib and pharmaceutically acceptable salts thereof are disclosed in WO0042012. Sorafenib is also disclosed in

WO0041698. Both these patents also disclose processes for the preparation of sorafenib.

Sorafenib is approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma) . The maximum tolerated does in humans is an oral administration of 400mg twice daily. References: WO0042012, WO0041698 (incorporated herein by refer^¬ ence) .

Sorafenib antagonizes activity of gene CG8222 (PDGF- and VEGF-receptor related) . Whole body and fat body-specific knock^¬ down of this gene resulted in a loss of trigylcerides in the fly. The human orthologue of this gene is KDR (kinase insert do- main receptor (a type III receptor tyrosine kinase. It functions as mediator of endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and traf^¬ ficking of this receptor are regulated by multiple factors, in^¬ cluding Rab GTPase, P2Y purine nucleotide receptor, integrin al- phaVbeta3 and T-cell protein tyrosine phosphatase.

Sorafenib may be administered orally and has a half life of 25-48 hours. The dosage can be between 50 and 600 mg (adult hu^¬ man dose), preferably about 200 mg.

Tanespimycin

Tanespimycin, also known as 17-allylamino- demethoxygeldamycin (17-AAG) and KOS-953, is an ansamycin anti^¬ biotic which acts as an anti-tumour agent. Specifically, Tane^¬ spimycin binds and inhibits Hsp90 (Heat shock protein 90) . Hsp90 is a protein chaperone that binds to signalling proteins, known as client proteins. These client proteins include key cancer- relevant targets such as mutated p53, Bcr-Abl, Her2, Akt, Raf-1, B-Raf, and others. Tanespimycin is able to disrupt the Hsp90- client protein complexes and lead to the degradation of the cli^¬ ent proteins. Tanespimycin and the related compound Alvespimycin (INN) also known as 17-dimethylamino- geldanamycin (17-DMAG) or KOS-1022 are less toxic analogues of geldanamycin (GA) .

Tanespimycin has been investigated for the treatment of pa^¬ tients with Relapsed-refractory Multiple Myeloma, Metastatic Papillary or Clear Cell Renal Cell Carcinoma, Recurrent Advanced Ovarian Epithelial or Primary Peritoneal Cavity Cancer, Metas^¬ tatic Breast Cancer and Refractory or Advanced Solid Tumours or Hematologic Malignancies.

Tanespimycin is water insoluble, and thus it is administered to patients intravenously using organic solvents such as DMSO. A formulation of tanespimycin, KOS-953, that contains Cremophory EL (polyethoxylated castor oil) rather than DMSO has also been developed. Recommended phase II doses of 295 mg/m2, 308 mg/m2, and 450 mg/m2 have been administered to patients.

Knock-down of the Drosophila gene CG1242 resulted in a re^¬ duction of triglyceride levels in the fly. The human orthologue of this gene is the heat shock protein HSP90AA1. HSP90 proteins are highly conserved molecular chaperones that have key roles in signal transduction, protein folding, protein degradation, and morphologic evolution. HSP90 proteins normally associate with other cochaperones and play important roles in folding newly synthesized proteins or stabilizing and refolding denatured pro^¬ teins after stress. HSP90AA1 is one of the two major cytosolic HSP90 proteins.

In preferred embodiments 17-N-Allylamino-17- demethoxygeldanamycin may be administered i.p., i.v., or oral, preferably i.p., e.g. at doses of 60, 40, and 26.67 mg/kg i.p. and oral doses of 40 mg/kg. Preferably the dose may be between 1 mg/kg of body weight to 500 mg/kg, preferably at least 20 mg/kg or even above 80 mg/kg.

S-17092

"S-17092" or "S 17092-1", (2S, 3aS, 7aS)-l{[(R, R) -2- phenylcyclopropyl ] carbonyl}-2- [ (thiazolidin-3-yl) carbonyl] octa- hydro-lH-indole, is a selective inhibitor of the enzyme Prolyl endopeptidase . This enzyme is involved in the metabolic break^¬ down of a number of neuropeptide neurotransmitters in the brain and so inhibiting the action of the enzyme increases the activ^¬ ity of these neuropeptides. This produces nootropic effects which make S-17092 a promising and novel treatment for neurode^¬ generative conditions such as Alzheimer's disease and Parkin^¬ son's disease. S 17092 might possess some mood-stabilizing po^¬ tential in addition to its cognition-enhancing properties.

S-17092 has been administered orally to patients at doses of 100, 400, 800 and 1200 mg once daily (Morain et al . , 2000).

Knockdown of the drosophila gene CG5355 resulted in a loss of triglyceride levels in the fly. Tissue specific deletion in the liver and fat body also lead to a reduction of triglyceride levels in the fly. A human orthologue of CG5355 is PREP. PREP (Prolyl endopeptidase) is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropep^¬ tides .

Lintopride

Lintopride (also referred to as Lintopril) is a 5HT-4 an^¬ tagonist with moderate SHT-3 antagonist properties. Lintopride has been shown in humans to increase the lower oesophageal sphincter (LOS) motility basal tone without affecting LOS physiological relaxation after swallowing and leads to an in- crease of peristaltic waves in the oesophagus.

It can be administered orally or intravenously and has been used at dosages of 0.1, 0.3, 0.5 mg/kg in humans.

Whole body and muscle specific knockdown of the Drosophila gene CG6919 lead to a reduction in triglyceride levels in the fly. The human orthologue of this gene is HTR4. This gene is a member of the family of serotonin receptors, which are G protein coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine) . The gene product is a glycosy^¬ lated transmembrane protein that functions in both the periph^¬ eral and central nervous system to modulate the release of vari^¬ ous neurotransmitters.

Fenoprofen

Fenoprofen, non-steroidal anti-inflammatory drug, is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic properties. Fenoprofen calcium is used for sympto^¬ matic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain.

Whole body, neuronal and liver specific knockdown of CG8451 lead to a reduction of fly triglyceride levels. This gene is an orthologue of the human gene SLC5A8. Inflammatory drugs such fenoprofen function as blockers of this transporter.

Fenoprofen is taken orally at doses ranging from 200mg up to a maximum recommended dose of 3.2g per day.

Sulfaphenazole

Sulfaphenazole is a sulfonamide antibacterial and a specific inhibitor of CYP2C9. It blocks the pro-inflammatory and athero^¬ genic effects of linoleic acid (increase in oxidative stress and activation of AP-1) mediated by CYP2C9.

Sulfaphenazole has been administered to patients by intra^¬ venous and intra-arterial perfusion (0.03 μg/100 ml tissue/min) (Giannarelli et al . , 2009).

Whole body and liver specific knockdown of the fly gene CG3466 resulted in a reduction of triglyceride levels. CG3466 is a member of the cytochrome P450 enzyme family. Sulfaphenazole functions as an inhibitor of cytochrome function.

Fluticasone

Fluticasone propionate (Ubizol) is a synthetic corticoster^¬ oid derived from fluticasone used to treat asthma and allergic rhinitis (hay fever) . It is also used to treat eosinophilic esophagitis. Fluticasone propionate is delivered as an aerosol formulation and is also available as a cream for the treatment of eczema and psoriasis.

A recent study has indicated that Fluticasone propionate functions as a Smoothened (Smo) agonist that activate Hedgehog signalling (Wang et al . , 2010) .

The maximum recommended dose for fluticasone propionate aqueous nasal spray is 200 micrograms daily. Intranasal admini^¬ stration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects re^¬ ported. Repeat oral doses up to 80 mg daily for 10 days in vol^¬ unteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated.

Rolipram

Rolipram is a phosphodiesterase IV inhibitor with antide^¬ pressant properties. It is an anti-inflammatory drug being stud^¬ ied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects. Other beneficial effects of rolipram include improved long term mem^¬ ory, increased wakefulness, and increased neuroprotection. Rol^¬ ipram shows promise in ameliorating Alzheimer's disease, Parkin^¬ son's disease and also in the regeneration of severed spinal cord axonal bodies.

Rolipram can be administered orally or intravenously usually at doses ranging from 0.001-10 mg per day.

Febuxostat

Febuxostat (INN) is an inhibitor of xanthine oxidase. Xan^¬ thine oxidase functions to successively oxidize both hypoxan- thine and xanthine to uric acid. Inhibition of xanthine oxidase by febuxostat reduces production of uric acid. Febuxostat is in^¬ dicated for use in the treatment of hyperuricemia and gout. The recommended dose is of 40 mg or 80 mg orally once daily.

Verapami1 , Norverapami1

Verapamil and its salt Verapamil Hydrochloride is an L-type calcium channel blocker of the Phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class 4 antiarrhythmic. The maximum recommended human daily dose is 480 mg/day by oral administration.

Further prefered compounds are associated with the gene CG9438 and the human orthologue CYP3A4 from the list of erlotinib, ge- fitinib and lapatinib:

Erlotinib

Erlotinib, preferably used in its hydrochloride salt form (trade name Tarceva) , is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of can^¬ cer. It is a tyrosine kinase inhibitor, which acts on the epi^¬ dermal growth factor receptor (EGFR) .

Gefitinib

Gefitinib (trade name Iressa) is an EGFR inhibitor drug used in the treatment of advanced non-small cell lung cancer (NSCLC) . Lapatinib

Lapatinib, preferably used in the form of lapatinib ditosy- late (USAN) (Tykerb/Tyverb, GSK) , is an orally active drug for treatment of breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which disrupts the HER2 growth recep^¬ tor pathway.

Further prefered compounds are associated with the gene CG8222 and its human orthologue KDR selected from the list of axitinib, pazopanib, and semaxanib (also known as Semaxinib or SU 5416) : Axitinib

Axitinib is a small molecule tyrosine kinase inhibitor. It has been shown to significantly inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumour types.

Pazopanib

Pazopanib is a multi-targeted receptor tyrosine kinase in^¬ hibitor. It has been approved for treatment of renal cell carci^¬ noma. Pazopanib may also be active in ovarian cancer and soft tissue sarcoma and in the treatment of non-small cell lung car^¬ cinoma .

Semaxanib (also known as Semaxinib or SU 5416)

Semaxanib is a tyrosine kinase inhibitor that has been with^¬ drawn from clinical trials after failing to show efficacy in the treatment of patients with advanced stage colorectal cancer. Further prefered compounds are associated with the gene CG6919 and its human orthologue HTR4 selected from the list of cis^¬ apride, mosapride, piboserod, prucalopride, tegaserod, tropise- tron, renzapride, and zacopride:

Cisapride

Cisapride is a gastroprokinetic agent, a drug which in^¬ creases motility in the upper gastrointestinal tract. Cisapride increases muscle tone in the esophageal sphincter in patients with gastroesophageal reflux disease. It has alos been used to treat bowel constipation.

Mosapride

Mosapride is a gastroprokinetic agent which accelerates gas^¬ tric emptying and is used for the treatment of acid reflux, ir^¬ ritable bowel syndrome and functional dyspepsia.

Piboserod

Piboserod (also known as SB 207266) is used for the treat^¬ ment of atrial fibrillation and irritable bowel syndrome. It is also being investigated as a treatment for heart failure

Prucalopride

Prucalopride treats the impaired motility associated with chronic constipation, thus normalising bowel movements.

Renzapride

Renzapride is a gastroprokinetic agent and antiemetic, which was being investigated for the treatment of constipation- predominant irritable bowel syndrome (IBS-C) . It is also poten^¬ tially effective for irritable bowel syndrome with alternating stool pattern (IBS-A) . However it failed to show efficacy over placebo in Phase III clinical trials and development was discon^¬ tinued .

Tegaserod

Tegaserod functions as a motility stimulant that stimulates gastrointestinal motility and the peristaltic reflex. It was ap^¬ proved for the treatment of irritable bowel syndrome and consti^¬ pation .

Tropisetron

Tropisetron is an antiemetic used to treat nausea and vomit^¬ ing following chemotherapy. It has also been used experimentally as an analgesic in the local treatment of tendinopathies and myofascial pain syndromes. Zacopride

Zacopride been shown to have many activities including anxiolytic and nootropic effects. It has also been shown to have antiemetic and pro-respiratory effects, both reducing sleep ap- noea and reversing opioid-induced respiratory depression in animal studies.

The above examples show that the inventive obesity tests re^¬ vealed pharmaceutical compounds that are well known to be thera^¬ peutically applicable for the treatment of human conditions and diseases. The compounds may now also be used for the treatment of obesity and associated secondary diseases such as diabetes or the metabolic syndrome. Of course the full list of compounds ac^¬ cording to table 1 provides new therapeutic concepts.

Further compounds to be used in any form of treatment, e.g. in combination with the above compounds or for use alone, ac^¬ cording to the present invention are selected from any one of

(5- (2-methoxy-5-chloro-5-phenyl) furan-2-ylcarbonyl) guanidine,

(E) -4- (2- (2- (N-acetyl-N- (4- methoxybenzenesulfonyl ) amino) stilbazole) ) 1-oxide, (melle- 4) cyclosporin, 1- ( 1-cyclohexylethylamino) -4-phenylphthalazine, 1- (2-methoxyphenyl) -4- (4- (2-phthalimido) butyl) piperazine, 15- deoxyprostaglandin J2, 17- (allylamino) -17-demethoxygeldanamycin, 17- (dimethylaminoethylamino) -17-demethoxygeldanamycin, 1- aminooxy-3-aminopropane, 1-beta-D-arabinofuranosyl-Cytosine, 1- carbamoyl-4-phenylpyrrolidone-2 , 1-Carboxyglutamic Acid, 1- deoxygalactonoj irimycin, 1-hydroxymethylmidazolam, 2- [2- [2- [2- [2-amino-3- (4-hydroxyphenyl) -1-oxo-propyl ] amino-l-oxo- ethyl] amino-l-oxo-ethyl ] amino-l-oxo-3-phenyl-propyl ] amino-4- methyl-pentanoic acid, 25-desacetylrifabutin, 2-AAF, 2-AAF, 2- AG, 2 -AG, 2-AP, 2-cyclopentyl-5- ( 5-isoquinolylsulfonyl) -6-nitro- ΙΗ-benzo (D) imidazole, 2-DG, 2-hydroxy-l-naphthylaldehyde isoni- cotinoyl hydrazone, 2-methoxyacetic acid [2- [2- [3- (1H- benzoimidazol-2-yl) propyl-methyl-amino ] ethyl] -6-fluoro-l- isopropyl-tetralin-2-yl ] ester, 2-methylarachidonyl-2 ' - fluoroethylamide, 2-phenyl-4-oxohydroquinoline, 2- propylquinoline, 3- (5- ( (4- (methylsulfonyl ) -1- piperazinyl) methyl) -lH-indole-2-yl) quinolin-2 (1H) -one, 3-AB, 3 ' - deamino-3 ' -hydroxydoxorubicin, 3-HF, 3-Methoxyoestradiol , 3-MF, 4- (4- (1-Amino-l-methylethyl) phenyl) -2- (4- (2-morpholin-4-yl- ethyl) phenylamino) pyrimidine-5-carbonitrile, 4 ' -epidoxorubicin, 4-methyl-N- (3- (4-methylimidazol-l-yl) -5- (trifluoromethyl) phenyl) -3- ( (4-pyridin-3-ylpyrimidin-2- yl) amino) benzamide, 4 ' -N-benzoylstaurosporine, 4PBA, 4-PCB, 5- (4 ' - (N-piperidinyl ) phenylazo) indazole, 5-bromo-4-chloro-3- indolyl beta-galactoside, 5-carboxamidotryptamine, 5- demethylovalicin, 5 ' -0- ( ( (2-decanoylamino-3- phenylpropyloxycarbonyl ) amino) sulfonyl) uridine, 6 ' -N- methylsisomicin, 7 HC, 7,8-BF, 7C3MT, 7-hydroxystaurosporine, 7- ketocholesterol , 8-Hydroxy-2- (di-n-propylamino) tetralin, 8- hydroxyguanosine, 9- (2-hydroxy-3-nonyl) adenine, 9-beta-D- erythrofuranosyladenine, 9-CRA, 9-hydroxy-risperidone, A-300-I, a-ADP, AAL 881, AATP, AB 2, abacavir, Abufene, Acenocoumarol , Acetidin, Acetorphan, acetoxymethyl-ester, Aclarubicin, ACNU, Acolen, ACON, actein, acteoside, Actihaemyl, Actosin, adalimu- mab, Adanon, ADMA, ADMA, Adofeed, Adrenor, Adrin, AEBSF, AEE 788, AG 1879, ajoene, Aklavin, alachlor, Alat, ALDA, Aldara, Al- docorten, alemtuzumab, Alendronate, Alfarol, Alfentanil, ALIMTA, aliskiren, Alii, Allnal, allylamino-demethoxy-geldanamycin, al- pha-neoendorphin, alternagin-C, Alvesco, alvimopan, Am 80,

Amatin, AMCHA, AMD 070, amentoflavone , Amiloride, Amine BB, Amiodarone, Amiodarone, amlexanox, Amlodipine, Ammo, Ampicillin, amprenavir, amrubicin, AMSA, amsonic acid, Anaboleen, Anan- damide, Anco, and-carboxyfluorescein-diacetate-succinimidyl- ester, Androstenediol , anilinyl, Anisomycin, ANSA, antibiotic G 418, antibiotic H107, antineoplaston A10, Antizol, APAP, APDC, Aphidicolin, Aphidicolin, Aphloiol, apicidin, Apigenin, ap- lidine, aprepitant, APRL, Apsor, aptiganel, Aralen, arctiin, Arecoline, Areether, argatroban, aripiprazole, Armor, Artein, ASTA, astatine, Astemizole, atazanavir, Atorel, atorvastatin, Atosil, Atovaquone, ATRA, Auluton, aureobasidin A, Aurothioglu- cose, AuTM, Axert, axitinib, Axsain, azacyclonol, Azadc, azamu- lin, azanediyl group, azaspirane, azelastine, azelnidipine, azi- doprazosin, Aziran, Azithromycin, Azor, Azur A, Azure B, BA (VAN) , Baclofen, Bagren, baicalein, Barnidipine, BAY 11-7085, Beflavin, Benidipine, benzoyl-staurosporine, beraprost, Ber- bamine, berberine, bergamottin, bergaptol, BESTATIN, beta- citronellol, beta-eudesmol , beta-funaltrexamine, beta-gamma- iminotriphosphate, bexarotene, Bezafibrate, BI D1870, biapi- genin, BIBF 1000, BIBW 22, bifeprunox, Bisoprolol, Bisphenol A- Glycidyl Methacrylate, bizelesin, Bleomycin, BM 41.440, BMS 310705, BMS-262084, BMS453, BMS-470539, BMY 7378, Borrelia- burgdorferi, bortezomib, bosentan, bosutinib, Bo-Xan, Brefeldin A, bremazocine, bryostatin, Budesonide, bufalin, Bumetanide, Bupivacaine, Buprenorphine, Buspirone, Buthionine, Buthionine Sulfoximine, cabergoline, CACP, Calcijex, Calcimycin, calphostin C, Calyculin, Camptothecin, candesartan, candoxatril, candoxat- rilat, Canef, CAPE, capsanthin, capsazepine, Carbamazepine, car- bamic acid, Cardiolipins , Cardioplegic Solutions, carebastine, carfentanil, Carisoprodol , CARNOSOL, carvacrol, carvedilol, Casodex, caspofungin, casticin, catechins, CD 437, Cefotaxime, Ceftazidime, celecoxib, Celiprolol, CEP 701, cephalomannine, cerivastatin, Cerulenin, Cetirizine, Cetirizine, cetuximab, CGS 26303, CGS 35066, CGS 35601, Chloramphenicol, chloroprocaine, Chlorzoxazone, chymostatin, cicaprost, ciglitazone, Ciguatoxins, Cillora, cilostazol, Cimetidine, CINK4, Cipol N, Ciprofloxacin, Ciprol, Cisapride, Citalopram, Citox, CJ-15161, Cladribine, cla- vosine B, clavulone II, clobazam, Clodronic Acid, Clofazimine, Clofibric Acid, Clomipramine, Clonazepam, Clonidine, clonidine- displacing substance, clopidogrel, clotiazepam, Clozapine, CMDBS 25, Co 2-1970, Colchicine, Cordanum, cornuside, costunolide, Co- tinine, Cotrim, coumarin, coumarin, coumarin, coumermycins , CP 31398, CRA 026440, CREBtide, Crestor, Crodacid, cryptotanshi- none, cryptoxanthin, Cyclandelate, cyclohexanecarboxylic acid (2- (4- ( 2 -bromo-5-methoxybenzyl) piperazin-l-yl) ethyl) - (2- trifluoromethoxyphenyl) amide, cyclopamine, cyclopiazonic acid, cycloprodigiosin, cyclosporin G, cyclotheonamide A, Cyproterone Acetate, Cystamine, cytarabine, D 21266, DA 8159, DABS, Dacarba- zine, DADA, DADSO, daidzein, Dalteparin, D-AM, danaproid, Dana- zol, Dapsone, Daral, Darifenacin, dasatinib, DAU 6285, Daunoru- bicin, dauricine, Dayfen, Dddd-PGD2, decursin, Deferoxamine, DEHP, dehydroaripiprazole, Dehydroepiandrosterone Sulfate, dehy- droxymethylepoxyquinomicin, Delavirdine, delphinidin, delta-1- pyrroline-5-carboxylate, delta8-THC, Denagard, denbinobin, deno- sumab, deoxyhypusine, deoxyverrucosidin, Depas, dephosphonocaly- culin A, Deproceptin, deramciclane, dermorphin, desethylchloro- quine, desloratadine, desmethylazelastine, Desmethyldeprenyl , desmethyl-tamoxifen, DEVD-CHO, dexecadotril , dexloxiglumide, Dextropropoxyphene, Diaben, Diacomit, diadenosine tetraphos- phate, Didanosine, dillapiol, Diltiazem, Dinoprostone, Dios- genin, diosmetin, dioxirane, Dioxolan, Dipyrone, Disopyramide, Ditiocarb, Dizocilpine Maleate, DNSC1, Doca, dofequidar,

Dolomin, Domperidone, Doxazosin, doxifluridine, Doxycycline, DPC 681, DPCPX, DPPH, Droxia, Drysol, duloxetine, Durapatite, Durs- banoxon, DX 9065a, Dxms, dynapen, Dynatra, dynorphin, dysidenin, dysprosium, dystrobrevin, E 10, EACA, ebastine, ebrotidine, Econ, econazole, ecteinascidin 743, ectoine, Edex, Edrophonium, efavirenz, efrapeptin, EGCg, EGRck, EHT 1864, eletriptan, Embe- lin, embellistatin, EMD 53998, EMD 61753, emetine, E-MIX 80, Emodin, Empecid, emtricitabine, enadoline, Enalapril, Enalapri- lat, Enediynes, Enelone, Enoximone, EPIB, Epicar, epicatechin gallate, epimedin C, Epoprostenol , Epostane, Epothilones, epoxy- bergamottin, epsilon-viniferin, eptifibatide, ergotamine, erio- calyxin B, erlotinib, erucin, Eryc, Eskazine, Estramustine, ET18-Ome, Etfc cpd, Ethacrynic Acid, Ethambutol, Etidronic Acid, Etodolac, Etoposide, etoricoxib, Etorphine, etravirine, Eufor, eumelanin, eupatilin, everolimus, Evex, Evodin, exenatide, Ex- tina, ezetimibe, F 11440, Fanchinine, F-Ara-A, febuxostat, fel- bamate, Felodipine, fenitrothion, fenofibric acid, Fenoprofen, Fenretinide, fexofenadine, fingolimod, fipronil, fisetin, FLCZ, Flecainide, Flesinoxan, flibanserin, Floxacillin, Fludeoxyglu- cose F 18, Flunarizine, fluorexon, Fluorouracil , Fluparoxan, Flupenthixol , fluvoxamine, fondaparinux, Fonofos, Format, For- skolin, fosamprenavir, Foscarnet, Frakefamide, fucoidan, ful- vestrant, Fura-2, furafylline, Furylfuramide, FYDE, Gambogic acid, gedunin, gefitinib, Geldanamycin, Gemfibrozil, genipin, Gentamicins, gepirone, Gestodene, GF 120918, GGTI 298, GI

129471, Ginkgo-biloba-extract , glabridin, GLCa, Glumin, Glycy- ron, glyox, Gnidimacrin, gossypetin, gossypol, GR 113808, grifo- lin, Grofo, Guggulsterone, gusperimus, Harzol, Hbim, HESPERETIN, Hexadimethrine, HMBA, hypsiziprenol A9, hypusine, hyrtioerectine A, ibandronic acid, IBMX, I-BOP, Ibotenic Acid, Icosapent, ICRF 193, idebenone, IDN 5390, Ifosfamide, Ifosfamide, IGF-1, Ilo- prost, imatinib, imidafenacin, imperatorin, Impulsin, Imrecoxib, Imutex, indazole, Indinavir, indiplon, indirubin-3 ' -monoxime, infliximab, inogatran, Ipral, Iprivask, ipsapirone, irbesartan, Iressa, irinotecan, irisolidone, irofulven, Irox, Ismo, Isobac, isochaihulactone, Isodonol, isoflavone, Isorhamnetin, isoste- viol, Isradipine, Istidina, ITF 2357, Itraconazole, Ivermectin, ixabepilone, J 113397, J 113397, j asplakinolide, juglone, juzen- taihoto, K 252, kaempferol, KAFA, kahweol, Kainic Acid, kami- untan-to, Kaolin, KB 2796, K-DR, Keloid, Kemi, ketazocine, Keto- pgflalpha, KKHA-761, KN 62, KN 93, KNK 437, KP372-1, K-PAM, KPMK, KR 31831, KRM 1648, K-SR, kurarinone, KYNA, L 685458, L797591, LAGA, Lamivudine, lamotrigine, lanreotide, lapachenole, lapatinib, LAQ824, laquinimod, latrunculin A, LBH589, le- flunomide, lenalidomide, Lendorm, Lentinan, Leukotriene B4, Leu- kotriene C4, Leukotriene D4, leukotrienes , Levonorgestrel , liarozole, lintopride, liquiritin, LMWH, LNAC, lonafarnib, lo- nidamine, Loperamide, lopinavir, Lopril, Loratadine, Lorazepam, Lorex, Losartan, Lovan, loxiglumide, L-T3, lupeol, luteolin, lu- tetium, Lutex, LY 117018, LY 293111, LY 293284, LY 303511,

LY231514, mahanine, Maleimides, Malix, manzamine A, maraviroc, MBC1, MCYST-LR, Mebumal, Medemycin, Medroxyprogesterone 17- Acetate, Melatol, meletin, melitten, meloxicam, Memantine,

Menatetrenone, MENT, Mephenytoin, Meprobamate, MeSAdo, mesala- mine, Mesaton, mesoglycan, Mesol, metazachlor, Meth, methanop- terin, Methorphan, Methoxsalen, methoxymorphinan, Methylpredni- solone, Methylthioinosine, Metkephamid, Metopiron, Metribolone, Miazine, miconazole, Mictonorm, Midazolam, Mifepristone,

miglustat, milbemycin, Mimosine, mirtazapine, Mit-C, mithramycin A, Mitoxantrone, MK-0524, MLN 944, Molsidomine, Monensin, mono- cillin I, monodansylcadaverine, mono-N-demethyladinazolam,

Monorden, MORIN, morphine-3-glucuronide, mosapride, motapizone, Motuporin, moxifloxacin, MRK 003, MTPA, Muran, Muscarine, N- (4- aminophenethyl ) spiroperidol , N- (4-aminophenyl) maleimide, N- (4- cyano-benzo (b) thiophene-2-carbonyl) guanidine, N- (8-amino-l- carboxyoctyl ) -alanyl-proline, (alpha) - (4-amino-4-deoxypteroyl) - (delta) -hemiphthaloyl-L-ornithine, N- (m-heptyl) -5-chloro-l- naphthalenesulfonamide, N-3-isoquinolinyl-2- ( (4- pyridinylmethyl) amino) benzamide, NABU, Naftalen, Naloxone,

Naltrexone, naltrindole, NAN-190 hydrobromide, nanchangmycin, Naphazoline, NARIGENIN, nateglinide, N- benzyloxycarbonylprolylprolinal , N-dehydroxyzileuton, N- desmethylclobazam, nedaplatin, Nefazodone, Nelfinavir,

nemonapride, neodymium, Neomycin, N-ethylmaleimide, netoglita- zone, neuromedin C, Neut, Nevirapine, Niacinamide, nicaraven, Nicardipine, Niceritrol, Nigericin, niguldipine, Nimodipine, NK 104, NMDA, N-methylsulfonyl- 6- (2-propargyloxyphenyl) hexanamide, NN 703, Nobiletin, NOC 18, Nociceptin, noralfentanil , Norbinal- torphimine, norcantharidin, Nordihydroguaiaretic Acid, Norethin- drone, noreximide, norfluoxetine, norlaudanosoline, Nortilidine, norverapamil, novobiocin, NPI 031L, NRDC, NSC 23766, NSC 295558, NSC 366140, NSC 663284, N-tert-butyl-3- [4- (2- methoxyphenyl) piperazin-l-yl] -2-phenylpropanamide, NU2058,

NU6102, nutlin 3, NVP-AEW541, obovatol, OC 144-093, ochratoxin A, Octreotide, Octreotide, O-demethyltramadol , O- desethylreboxetine, oenothein B, Ogen, OH-pro, Oktan, Olamine, olanzapine, oleandrin, oleylamide, olmelin, olomoucine, Olymp, omalizumab, omapatrilat, omega-N-Methylarginine, Omeprazole, omeprazole sulfone, Ondansetron, ONO 1301, Optef, Org 31540, Or- phenadrine, OSI 930, OSU 03012, Ouabain, ovalicin, Ovex, ox- aliplatin, oxatomide, oxcarbazepine, Oxidopamine, oxymatrine, Oxytrol, Paclitaxel, palytoxin, pamidronate, p-Aminohippuric Acid, panaxadiol, pantoprazole, PAPP, Parthenolide, Patulin, pa- zopanib, PCSO, PD 169316, PD 173074, PD 98059, PDBU, Pec- tenotoxin II, pegvisomant, Pemetrexed, pentosidine, Pentoxifyl^¬ line, Peplomycin, Pepstatin A, Perazine, Perillol, Perindopril, perylene bisimide, phen, phen, phenanthrene, phenothiazines , Phenprocoumon, Phenytoin, pheophorbide a, phloretin, Picibanil, picric acid, picropodophyllin, pidotimod, pifithrin, pindobind, pioglitazone, Piroxicam, plumbagin, Pluronic p 85, PMPA, PMSF, posaconazole, PP-IX, Pragmoline, Pravastatin, Prazosin, PRDL, Prednisone, preussin, Primidone, Proadifen, Procasil, Proceto- fen, Prodigiosin, Prodix, Promegestone, Propofol, prostaglandin Al, prostaglandin D2, prostaglandin El, prostaglandin F2alpha, prostaglandin H2, prostaglandin J2, prostaglandins, prostaglandins G, prostratin, prucalopride, prunustatin A, Pseudohypericin, pseudolaric acid B, psilocybin, Psoralens, PTAP, PTX-B, puer- arin, Pugnac, p-XSC, Pyrethrins, pyrvinium, quercitrin, quetiap- ine, Quicifal, quinupristin-dalfopristin, R 101933, rabeprazole, radester, Raloxifene, ramiprilat, rebamipide, reboxetine, re- mifentanil, renzapride, repaglinide, Requip, Revex, Rhodinal, Riacon, Ribavirin, Rifabutin, Riluzole, rimorphin, risedronic acid, risperidone, Ritodrine, Ritonavir, rituximab, RMI 12330A, Ro 13-8996, Ro 64-0802, Robitet, Rolipram, romidepsin, ropiva- caine, Roquefortine, roscovitine, rosiglitazone, rosmarinic acid, rosuvastatin, Rozevin, RPR 121056, Rulid, rutecarpine, Ru^¬ tin, S 17092-1, S 9788, S azabisabolene, Safingol, SAHA, sain- topin, Salicin, salinomycin, salinosporamide A, salubrinal, salvin, salvinorin A, samarium, sampatrilat, sangivamycin, Sa- quinavir, Sarasar, sarizotan, SB 203580, SB 207266, SB 216763, SB 225002, SB 415286, SB-649915, SB-706375, SCH 66712, schizan- drin B, SCIO-469, scoparone, Sediel, selamectin, Selegiline, Se- rad, sesamin, sevoflurane, Sildenafil, silybin, Sizofiran, so- falcone, sorafenib, SP 100030, sparfloxacin, spiradoline, spira- prilat, spirogermanium, SR 48692, SR 59230A, SRI 63-154, SRIH, ST 1481, STA 5326, stachybotrydial , Stanozolol, Stavudine, SU 1498, SU 5416, SU 5614, SU 6656, SU 6668, SU 9516, Sucralfate, Sufentanil, Sulem, Sulfamerazine, Sulfamethazine, sulfamide, Sulfaphenazole, Sulfoximine, Sulindac, sultopride, Sumatriptan, sunitinib, sural, T 0901317, TAC 101, Tacrolimus, Tamogel, tam- sulosin, tandospirone, Tangeretin, tanshinone, tariquidar, Tase- ron, Taurolin, TAXOTERE, tazarotene, TBDZ , TBHQ, TCDD, Tegafur, tegaserod, telithromycin, telmisartan, temozolomide, temsi- rolimus, Teniposide, Terfenadine, Teriparatide, Tetraprenol, TG101209, thalicarpine, Thapsigargin, Theaflavin, Thiazolidin- ediones, thiocoraline, thioridazine, Thiorphan, thromboxane B2, thulium, thymalfasin, Thymopentin, thymoquinone, Ticlopidine, Tilidine, tipifarnib, tipranavir, tirilazad, TKI-31, Tmndga, TMPN, Toddalin, Todralazine, tofisopam, Tolterodine, topiramate, Topotecan, Toremifene, Toxaphene, Tramadol, Tramat, trandola- pril, Trapidil, trapoxin A, trastuzumab, Trazodone, Tremode, triazolam, triazolobenzodiazepines , tributylstannane,

trichostatin A, trichostatins , Trifluoperazine, trioctyl

phosphine oxide, Triolein, triptolide, TRK 820, troglitazone, Troleandomycin, tropisetron, Trospium chloride, Tunicamycin, ty- lophorine, Tylox, tyrphostin AG-490, tyvelose, U 0126, U 69593, Ubizol, UH 301, Usaf B-12, USAN, Valproic Acid, valsartan, val- spodar, vandetanib, vapreotide, venlafaxine, Verapamil, verlu- kast, verrucosidin, versipelostatin, VGA1155, Vigil, vincaleu- koblastine, vincristine, Vindesine, vinorelbine, Visken, Viviq, voriconazole, vorozole, vulnibactin, Wakil, Warfarin, Wartman- nin, WAY 100635, Wogonin, WR 1065, WS 79089B, xanthohumol, Xaxa, ximelagatran, Xylit, Y 27632, YM-201627, YM-231146, zacopride, zafirlukast, ZD 4190, zeaxanthin, Zeldox, zileuton, Zimco, zin- cov, ZK 112993, ZM323881, zopiclone, ZSTK474 , Zymosan, or a combination thereof. These compounds interact with newly identified key regulators of fat deposit functions, triglyceride circula^¬ tion and obesity. Mechanistically the inventive treatments in^¬ volves the modulation of the genes and gene function or interac- tion with the gene products, in particular proteins, of the genes listed in table 1.

According to the investigation described herein it was found that these compounds modify at least one gene selected from the drosophila genes CG30184, CG10369, CG32401, CG2374, CG8693, CG14909, CG13299, CG7847, CG30462, CG30462, CG15169, CG1650, CG6577, CG30491, CG4373, CG10407, CG2198, CG6356, CG5744,

CG9506, CG31169, CG1728, CG9220, CG15625, CG5550, CG13088,

CG13188, CG14968, CG1503, CG1666, CG14869, CG2702, CG2984,

CG4394, CG9922, CG14529, CG17781, CG17781, CG9153, CG15178, CG5641, CG3879, CG15579, CG1422, CG6299, CG8107, CG7103,

CG10617, CG30360, CG32971, CG32336, CG31036, CG12602, CG9676, CG1433, CGllOO, CG31697, CG7095, CG2165, CG10230, CG10916,

CG3274, CG18767, CG5072, CG3396, CG15582, CG16826, CG6788,

CG9487, CG1888, CG4637, CG15162, CG5719, CG2254, CG4695,

CG14936, CG17867, CG15646, CG5402, CG15095, CG8250, CG18030, CG14303, CG14164, CG14677, CG12105, CG17440, CG32459, CG11404, CG8954, CG13138, CG9056, CG12997, CG12997, CG5436, CG14330, CG10809, CG1622, CG3893, CG1112, CG31690, CG12664, CG13679, CG17556, CG10062, CG31744, CG9760, CG1555, CG14375, CG32170, CG4271, CG32234, CG7287, CG14341, CG30486, CG31692, CG31421, CG5467, CG30065, CG9086, CG1688, CG17026, CG4415, CG10343,

CG15388, CG13984, CG3313, CG13116, CG4662, CG6919, CG17841, CG30411, CG9053, CG1180, CG14166, CG13125, CG13344, CG1490, CG2867, CG5591, CG14362, CG1531, CG15390, CG6689, CG14234,

CG14265, CG5674, CG3917, CG8257, CG9028, CG1722, CG18402,

CG7082, CG11797, CG3663, CG16704, CG31172, CG31219, CG1363, CG6721, CG5688, CG8527, CG13137, CG6612, CG6947, CG7737, CG1705, CG14704, CG10300, CG3597, CG3425, CG2540, CG6856, CG12259,

CG4583, CG3843, CG9634, CG3809, CG9295, CG9485, CG11555,

CG11601, CG14095, CG10166, CG2852, CG14164, CG14164, CG2898, CG3162, CG6603, CG8721, CG17742, CG14127, CG8665, CG9438,

CG32113, CG32353, CG4957, CG33558, CG11570, CG32669, CG11575, CG30271, CG7830, CG31061, CG2076, CG17596, CG6824, CG17921, CG12875, CG13020, CG13972, CG13673, CG10772, CG8079, CG13127, CG9144, CG8979, CG7097, CG11768, CG10632, CG14903, CG1874,

CG33466, CG3367, CG4851, CG17985, CG31229, CG3260, CG13023, CG11125, CG17184, CG31812, CG13360, CG30075, CG30183, CG7485, CG5495, CG5495, CG7065, CG13202, CG7779, CG9322, CG7091,

CG16758, CG5071, CG4920, CG1516, CG9554, CG10101, CG3004, CG7796, CG10152, CGI 8741, CG8444, CG11425, CG10128, CG10542, CG11878, CG14434, CG12345, CG2091, CG31459, CG13319, CG7177, CG7776, CG15005, CG31605, CG7213, CG17283, CG18268, CG3017, CG7567, CG32091, CG9695, CG8222, CG1515, CG8256, CG1975,

CG32467, CG3817, CG4038, CG6193, CG1572, CG8117, CG3526, CG7099, CG18525, CG9198, CG30470, CG17273, CG31439, CG1387, CG9952, CG6580, CG10840, CG13221, CG8202, CG8786, CG7199, CG11663,

CG12683, CG31161, CG8009, CG17202, CG1683, CG17335, CG33204, CG14694, CG11229, CG16836, CG12209, CG18414, CG13475, CG11621, CG13332, CG11756, CG11133, CG18586, CG4944, CG3213, CG4152, CG6147, CG8515, CG5827, CG12691, CG8308, CG13807, CG2260,

CG30004, CG4247, CG4247, CG5739, CG4202, CG4264, CG5245,

CG13707, CG3523, CG10686, CG9565, CG4111, CG14673, CG31132, CG5355, CG32149, CG8443, CG17461, CG8190, CG13744, CG9258,

CG6043, CG1759, CG8534, CG14792, CG8451, CG8654, CG12806,

CG14938, CG9399, CG10542, CG13168, CG31845, CG6277, CG17819, CG2818, CG1688, CG13868, CG17736, CG7546, CG31693, CG12897, CG2146, CG3440, CG3696, CG12426, CG18319, CG18279, CG18279, CG3054, CG2145, CG3825, CG9781, CG13423, CG12030, CG14911,

CG3911, CG6122, CG7206, CG8566, CG30476, CG9470, CG6127, CG5381, CG12505, CG1279, CG32140, CG12184, CG31364, CG1963, CG5484, CG4634, CG9748, CG32442, CG1921, CG18740, CG1242, CG9946,

CG11121, CG3497, CG6817, CG30080, CG1171, CG11430, CG10691, CG13281, CG11352, CG3839, CG14368, CG14024, CG9936, CG11505, CG11906, CG1263, CG14011, CG11339, CG12015, CG30389, CG17331, CG15432, CG15507, CG14842, CG3906, CG17754, CG5289, CG5378, CG5625, CG6156, CG13243, CG8239, CG1821, CG7762, CG3108, CG8053, CG3605, CG4207, CG8431, CG9098, CG5270, CG5595, CG6064, CG6967, CG7134, CG7549, CG6892, CG10687, CG10712, CG11981, CG12770, CG15599, CG18563, CG7770, CG6322, CG3806, CG3980, CG6054,

CG7292, CG3992, CG2998, CG8337, CG13194, CG5147, CG16903,

CG11202, CG10084, CG12323, CG31484, CG6949, CG7352, CG10728, CG11376, CG32210, CG7109, CG8615, CG9160, CG8298, CG15115,

CG1965, CG12595, CG15321, CG6009, CG11267, CG4453, CG3971,

CG17255, CG32791, CG14016, CG14016, CG1740, CG32667, as well as their human orthologues. According to the present invention function of at least one of these genes is modified by the in^¬ ventive compounds, in particular the small molecules given in table 1. In preferred embodiments the compound modulates at least two, three, four, five or six or more of these genes (or orthologues) . Further compounds suitable to modulate gene func^¬ tion include the administration of therapeutic proteins or nu^¬ cleic acids, such as transgenes or inhibitory nucleic acids

(RNAi molecules, siRNA, antisense RNA or DNA) . Such interfering nucleic acids bind messages of the genes leading to degradation and reduced gene expression. Preferred therapeutic proteins in^¬ clude the gene products of these genes (as agonists) or antibod^¬ ies which specifically bind these proteins (as antagonists, but also as agonists if protein activity is increases - such as by binding and blocking an inhibitor binding site) . The inventive compounds can act as either agonist by increasing the gene func^¬ tion (via mRNA regulation or interaction with the protein) of a protein in the enzymatic pathway of any one of the above listed genes or an antagonist in said pathways. The antagonizing or ac^¬ tivating (agonist) activity of the compounds acts preferably on the identified obesity genes (including their gene product) themselves or on a binding partner thereof. In preferred embodi^¬ ments antagonists of the obesity genes are used.

Among the genes that can be targeted are also potential regulators of feeding control. For instance, odorant receptor genes 10a, 56a, 65a, 67a, 83cd, CG10407 and gustatory receptors 98b and 36b can be targeted, in particular, suppressed or an^¬ tagonized. Also, the dopamine receptor DopR2, two octopamine re^¬ ceptors (TyrR and oa2) and the Nmda-receptor associated protein Nmdal In addition, altered fat deposition was observed in re^¬ sponse modification of genes involved in glucose/lipid mobiliza^¬ tion including fructose-1 , 6-bisphosphatase (fbp) , the two mem^¬ bers of the glycerol phosphate shuttle (CG31169 and Gpo-1) , mi^¬ tochondrial acyl-carrier protein 1 (mtacpl) , ADP/ATP translocase 2 (Ant2) , pyruvate carboxykinae (CG1516), and fatty-acid syn^¬ thetase (fasn) . Further examples of genes to be modified accord^¬ ing to the present invention includes the Drosophila orthologues of glucagon (akh) , the insulin receptor (dlnR) , as well as the downstream kinases PI3-kinase (dPI3K) , ribosomal-S 6-kinase

( dRSK) , the CREB-coactivator dTORC, and the critical TOR- signaling constituent dTSC-1, Drosophila homologues of the critical early adipogenic regulators NCORl/2, Jagl/2, and TAK1, or the metabolic regulators CRTCl/2 and pyruvate carboxylase

(PC) . To all of the drosophila genes the present invention has identified human orthologs (table 1) that can be targeted by the inventive use of the theraputic compounds.

According to the present invention all genes listed in table 1, those shown in example 1.2, in particular those illustrated in examples 1.3, 1.4 or 1.5, can be modified by therapeutic ad^¬ ministration of suitable compounds. Preferred genes to be modi^¬ fied according to the present invention are those discussed above, as well as the LSD (Lipid Storage Droplet) and LPD (LiPid Depleted) genes, the Drosophila insulin like peptides (Hp's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp) , bubblegum (bbg) , and the Drosophila SREBP homo^¬ logue, HLH106, CG8451, of course, as well as their human

orthologues .

Table 1: List of therapeutic compounds: Small Molecule: name of compound (see list of synonyms below), Human ortholog: human gene name of therapeutic target, Human Entrez ID: gene ID, Dro^¬ sophila: ortholog Drosophila gene ID, Type: Type of interaction Molecule (0: Obesity - obesity pathway interaction, B: validated binding partner)

Small Mole- Human Orthologs Human Entrez ID Drosophila Ty cules pe

(5- (2- CYP3A4 1576 CG9438 0 methoxy-5- chloro-5- phenyl) furan- 2- ylcar- bonyl) guanidi

ne

(E)-4-(2-(2- ABCB1 5243 CG3879 0

(N-acetyl-N-

(4- methoxyben- zenesul- fonyl ) amino ) s

tilbazole) )

1-oxide

(melle- FK6 8468 CG375 0

4 ) cyclosporin

1-(1- CYP3A4 1576 CG9438 0 cyclohexy- lethylamino ) - 4- phenylphtha- lazine

l-(2- HTR1A 3350 CG7485 0 methoxy- phenyl) -4- (4- (2- phthalimido ) b

utyl) piperazi

ne

15- JUN, JUND, LT1 , KDR 3725,3727,2321,37 CG2275, CG2275, CG8 0 deoxypros- , TFDP2, JUNB, APC, H 91,7029,3726,324, 222 , CG8222 , CG4654 taglandin J2 GF 3082 , CG2275 , CG6193 , CG

13744

17- CDK6,HSP90AA1,CDK 1021,3320,1019,33 CG5072 , CG1242 , CG5 0

(allylamino) - 4 , HSPA4 , DNAJB1 , CC 08,3337,595,3791, 072 , CG6603, CG1057 17- ND1 , KDR, EIF2S1 , AB 1965,5243 8 , CG9096, CG8222 , C demethoxy- CB1 G9946,CG3879 geldanamycin

17- HSPH1,HSPA4, DNAJB 10808,3308,3337,2 CG6603 , CG6603 , CGI 0

(dimethylami- 1 , FGF2 , HSP90AA1 247,3320 0578 , CG4608 , CG124 noethyl- 2

amino) -17- demethoxy- geldanamycin

l-aminooxy-3- ODC1 4953 CG8721 0 aminopropane

1-beta-D- JUN 3725 CG2275 B arabinofu- ranosyl-

Cytosine

1-carbamoyl- PSMD2 5708 CG7762 0

4- phenylpyr- rolidone-2

1- GLA 2717 CG5731 B

Carboxyglu- tamic Acid

1- GLA 2717 CG5731 B deoxygalac- tonoj irimycin

1- CYP3A4 1576 CG943£ 0 hydroxy- methylmida- zolam

2- [2-[2-[2- MME 4311 CG9565 0 [ 2-amino-3- hydroxy- phenyl) -1- oxo- propyl ] amino- 1-oxo- ethyl ] amino- 1-oxo- ethyl ] amino-

1-oxo-3- phenyl- propyl ] amino-

4-methyl- pentanoic

acid

25- CYP3A4 1576 CG943i

desacetylri- fabutin

2-AAF RAC1 5879 CG2248 B 2-AAF ABCBl 5243 CG3879 0 2 -AG RAC1 5879 CG2248 B 2 -AG FAAH 2166 CG6007 B 2-AP PLG 5340 CG13744 0 2- HSPA5, ABCBl, FGF2 3309,5243,2247 CG5436,CG3879,CG4 B cyclopentyl- 608

5- (5- isoquinolyl- sulfonyl) -6- nitro-lH- benzo (D) imida

zole

2-DG CCND1,CCNB1,CDK4 595,891,1019 CG9096,CG3510,CG5 0 072

2-hydroxy-l- CCND1 595 CG9096 B naphthylalde- hyde isoni- cotinoyl hy- drazone

2- CYP3A4 1576 CG9438 0 methoxyacetic

acid [2- [2- [3- (1H- benzoimida- zol-2- yl ) propyl- methyl- amino ] ethyl ] - 6-fluoro-1- isopropyl- tetralin-2- yl] ester

2- FGF2 2247 CG4608 B methylarachi- donyl-2 ' - fluoroethyla- mide

2-phenyl-4- CDC2 983 CG5363 B oxohydroqui- noline

2- ABCB1 5243 CG3879 0 propy1quino- line

3- (5-((4- KDR 3791 CG8222 0 (methyl sul- fonyl) -1- piperaz- inyl ) methyl ) - lH-indole-2- yl ) quinolin- 2 (1H) -one

3-AB JUND, JUNB, JUN 3727,3726,3725 CG2275, CG2275, CG2 B 3 ' -deamino- ABCB1 5243 CG3879

3'- hydroxy- doxorubicin

3-HF ABCB1 5243 CG3879 0 3- CYP3A4 1576 CG9438 0

Meth- oxyoestradiol

3-MF OPRM1 4988 CG7285 B

4- (4- (1- KDR 3791 CG8222 0 Amino-1- me- thylethyl ) phe

nyl)-2-(4-(2- morpholin-4- yl- ethyl ) phenyla

mino) pyrimidi

ne-5- carbonitrile

4 ' - CSE1L, ABCB1 1434, 5243 CG13281,CG3879 0 epidoxorubicin

4-methyl-N- CYP3A4 1576 CG9438

(3- (4- methy1imida- zol-l-yl) -5- ( trifluoro- methyl) phenyl

)-3-( (4- pyridin-3- ylpyrimidin- 2- yl) amino) benz

amide

4'-N- CDK2 1017 CG5363

benzoyl- staurosporine

4PBA HSPA8,HSP90B1,HSP 3312,7184,3309 CG31449, CGI 242, CG 0

A5 5436 4-PCB CYP24A1 1591 CG6042

5- (4 ' - (N- CDK2, CCNA2 1017, CG5363, CG3510 piperid- inyl) phenylaz

o ) indazole

5-bromo-4- CYP3A4 1576 CG943i

chloro-3- indolyl beta- galactoside

5- HTR1A 3350 CG7485

carboxamidot- ryptamine

5- METAP2 10988 CG4008

demethy- lovalicin

5'-0- ( ( (2- FYN 2534 CG7524

de- canoylamino- 3- phenylpropy- loxycar- bonyl ) amino ) s

ul- fonyl ) uridine

6 ' -N- FBN2 2201 CG3936

methyl- sisomicin

7 HC CCND1 595 CG9096 B 7, 8-BF CYP3A4, CYP3A7 1576, 1551 CG9438, CG943? 0 7C3MT G0RASP1,CYP3A4 64689, 1576 CG7809, CG943? 0 7- CDK4, CDK2, CDK6, CD 1019,1017,1021,9? CG5072,CG5363,CG5 B hydroxys- C2, ABCB1, PDPK1, CC 3, 5243, 5170, 890 072,CG5363,CG3879 taurospori NA2 ,CG1210,CG3510

7- GORASP1, DYNLL1 64689,8655 CG7809, CG5450 B ketocholes- terol

8-Hydroxy-2- HTR1A 3350 CG7485

(di-n- propylami- no) tetralin 8- RPS3,CDK4 6188, 1019 CG6779, CG5072 0 hydroxy- guanosine

9- (2-hydroxy- CCND1 595 CG9096

3- nonyl) adenine

9-beta-D- MTAP 4507 CG4802

erythrofu- ranosy- ladenine

9-CRA FBN2 , JUND, JUNB, HS 2201, 3727, 3726, 33 CG3936,CG2275,CG2 B

PA4 , JUN, CCND1 , CYP 08, 3725, 595, 1594, 275,CG6603,CG2275 27B1, CYP24A1 1591 ,CG9096,CG6042,CG

6042

9-hydroxy- CYP4F3 4051 CG3466 B risperidone

A-300-I JUNB, CDK4 , JUND, NC 3726, 1019, 3727, 96 CG2275,CG5072,CG2 O

OR1, DOCK8,OPRMl,E 11, 81704, 4988, 195 275, CG7951, CG1137 GR1 , ABCB1 , CCND1 , J 8, 5243, 595, 3725, 2 6,CG7285,CG7847,C UN, GATA4 626 G3879,CG9096,CG22

75, CG3992

a-ADP PLAT 5327 CG13744 O AAL 881 KDR 3791 CG8222 O AATP CYP3A4 , CYP4 F3 , RAC 1576, 4051, 5881 CG9438,CG3466,CG2 B

3 248

AB 2 GLA, JUN 2717, 3725 CG5731, CG2275 B abacavir KLHL1 , HSPA4 , ABCB1 57626, 3308, 5243 CG17754,CG6603,CG O

3879

Abufene ECE1 1889 CG9565 O Acenocoumarol NF2 4771 CG14228 B

Acetidin ABCB1, SERPINB1 5243, 1992 CG3879, CG9456 B

Acetorphan MME 4311 CG9565 O acetoxy- EGR1 1958 CG7847 O methyl-ester

Aclarubicin MYB 4602 CG9045 B

ACNU ABCB1 5243 CG3879 O

Acolen CYP3A4 1576 CG9438 O

ACON CYP3A4, SF4, CCND1, 1576,57794,595,52 CG9438 , CG31550 , CG O

ABCB1, ABCB4 43,5244 9096,CG3879,CG387

9 actein CCND1,CDK4 595, 1019 CG9096, CG5072 0 acteoside CCND2 , CCND1 , CCND3 894, 595, 896 CG9096,CG9096,CG9 B

096

Actihaemyl PCSK5 5125 CG10772 0 Actosin PDGFB 5155 CG7103 0 adalimumab PSMD12 5718 CGllOO O Adanon ABCB1 , OPRM1 , CYP3A 5243, 4988, 1576 CG3879,CG7285,CG9 O

4 438

ADMA KDR 3791 CG8222 O ADMA HSP90AA1 3320 CG1242 O Adofeed SLC5A8, PLG, SLC5A1 160728, 5340, 15996 CG32669,CG13744,C O

2 3 G32669

Adrenor RAC1, TBXAS1, JUND, 5879, 6916, 3727, 51 CG2248,CG3466,CG2 B

PDGFB, HSPB6, JUNB, 55, 126393, 3726, 30 275,CG7103,CG4183 HGF, FYN, MYH7 , JUN 82, 2534, 4625, 3725 ,CG2275,CG13744,C

G7524,CG2146,CG22

75

Adrin CCNE2,RAC1, FOXD3, 9134, 5879, 27022, 3 CG3938,CG2248,CG3 B

HSP90AA1, CCND1, EC 320, 595, 1889, 5243 668,CG1242,CG9096 El, ABCB1, PLAT,OPR , 5327, 4988 ,CG9565,CG3879,CG Ml 13744, CG7285

AEBSF PLG, HSPA5,NC0R1 5340, 3309, 9611 CG13744,CG5436,CG B

7951

AEE 788 KDR 3791 CG8222 O

AG 1879 KDR 3791 CG8222 O aj oene CCNB1 891 CG3510 B

Aklavin QRSL1 55278 CG6007 B alachlor CYP3A4, CYP3A7 1576, 1551 CG9438, CG9438 O

Alat CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O

ALDA PSMD2 5708 CG7762 O

Aldara TSC1 7248 CG6147 O

Aldocorten SER- 462,27022,3480, 90 CG9456,CG3668,CG1 B

PINC1, FOXD3, IGFIR 68, 65125, 65266, 13 842,CG5550,CG7177 , ANGPTL1 , WNK1 , WNK 57, 1958, 4051 ,CG7177,CG14820,C 4,CPA1,EGR1,CYP4F G7847,CG3466

3

alemtuzumab CCND2 894 CG9096 B Alendronate CYP27A1,BEST1 1593, 7439 CG6042, CG6264 B Alfarol BEST1 7439 CG6264 B Alfentanil 0PRM1,CYP3A4 4988, 1576 CG7285, CG9438 O ALIMTA TBXAS1 6916 CG3466 B aliskiren MAPT, ATP6AP2, CYP3 4137, 10159, 1576 CG31057,CG8444,CG O

A4 9438

Alii CPB2 1361 CG14820 B

Allnal HSPA4 3308 CG6603 O allylamino- HSP90AA1 3320 CG1242 O demethoxy- geldanamycin

alpha- OPRK1 4986 CG7285 B neoendorphin

alternagin-C KDR 3791 CG8222 O

Alvesco CYP3A4 1576 CG9438 O alvimopan OPRM1 4988 CG7285 B

Am 80 JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2 B

275

Amatin SMARCA4 , SMARCA2 6597, 6595 CG5942, CG5942 B

AMCHA PLG 5340 CG13744 O

AMD 070 CYP3A4 1576 CG9438 O amentoflavone GORASPl 64689 CG7809 B

Amiloride CCNB1, PDPK1,0DC1, 891, 5170, 4953, 534 CG3510,CG1210,CG8 O

PLG 0 721,CG13744

Amine BB SERPINB1 1992 CG9456 B

Amiodarone SLC5A8 160728 CG32669 O

Amiodarone SLC5A8, CYP3A4 160728, 1576 CG32669,CG9438 O amlexanox FGF1 2246 CG4608 B

Amlodipine PLAT, CYP3A4, JAK2, 5327, 1576, 3717, 59 CG13744,CG9438,CG O

CCND1, ABCB1 5, 5243 1594,CG9096,CG387

Q

Ammo MBL2 4153 CG7763 B

Ampicillin PLG 5340 CG13744 O amprenavir ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 O amrubicin ABCB1 5243 CG3879 O

AMSA TOP2B 7155 CG10223 B amsonic acid CDC2 983 CG5363 B

Anaboleen CYP24A1,SNAI2,CYP 1591, 6591, 1594, 52 CG6042,CG3758,CG6 B

27B1, ABCB1, CCND1, 43, 595, 2252, 890, 3 042,CG3879,CG9096

FGF7, CCNA2, IGF1R, 480, 3725 ,CG4608,CG3510,CG

JUN 1842, CG2275

Anandamide CDK2, HTR1A, FAAH 1591, 6591, 1594, 52 CG6042,CG3758,CG6 B

43, 595, 2252, 890, 3 042,CG3879,CG9096 480, 3725, 1017, 335 ,CG4608,CG3510,CG

0,2166 1842,CG2275,CG536

3,CG7485,CG6007

Anco ABCB1 , CYP27A1 , GOR 5243, 1593, 64689, 3 CG3879,CG6042,CG7 B

ASP1, HSPA8,MAPT 312, 4137 809,CG31449,CG310

57

and- CCND1 595 CG9096 B carboxyfluo- rescein- diacetate- succinimidyl

ester

Andros- KSR1 8844 CG2899 B tenediol

anilinyl FLT1 2321 CG8222 O

Anisomycin JUN, PSMD12, EGR1 3725, 5718, 1958 CG2275,CG1100,CG7 O

847

ANSA HSP90AA1 3320 CG1242 O antibiotic G HSPB2,CCNA2,HSPB1 3316, 890, 3315 CG14207,CG3510,CG B 418 14207

antibiotic PSMD12 5718 CGllOO O H107

antineoplas- ATF2 , MAPT , JUN, PDC 1386, 4137, 3725, 51 CG30420,CG31057,C O ton A10 D2, GSK3B, ABCB1, GL 34, 2932, 5243, 2717 G2275, CG326, CG262

A, MAGT1 , HGF , 84061, 3082 1,CG3879,CG5731,C

G7830,CG13744

Antizol Pll 8909 CG2145 O

APAP CYP3A4 1576 CG9438 O

APDC MAGT1 , JUNB, HGF, JU 84061, 3726, 3082, 3 CG7830,CG2275,CG1 B

N, DNAJB1, IGF1R, GO 725, 3337, 3480, 646 3744, CG2275, CG105

RASP1, ABCB1, JUND 89, 5243, 3727 78,CG1842,CG7809,

CG3879, CG2275

Aphidicolin POLS 11044 CG11265 B Aphidicolin POLS, JUN 11044, 3725 CG11265, CG2275 B Aphloiol GORASP1 64689 CG7809 B apicidin ABCB1,CDK2,CDK4,C 5243, 1017,1019,59 CG3879,CG5363,CG5 B

CND1, CCND3 5,896 072,CG9096,CG9096

Apigenin CDC2, ABCB1, JUNB, J 983, 5243, 3726, 372 CG5363,CG3879,CG2 B

UN, GORASP1, CCND1, 5, 64689, 595, 3727, 275,CG2275,CG7809

JUND, FBRS, CDK4, CD 64319, 1019, 1017,8 ,CG9096,CG2275,CG K2, CCNA2, HGF, CCNB 90, 3082, 891 9056,CG5072,CG536

1 3,CG3510,CG13744,

CG3510

aplidine JUNB, JUN, RACl , CYP 3726, 3725, 5879, 40 CG2275, CG2275, CG2 B

4 3, CYP3A4, JUND 51, 1576, 3727 248,CG3466,CG9438

,CG2275

aprepitant CYP3A4 1576 CG9438 O

APRL SSTR4, PCSK7, PIK3C 6754, 9159, 5286, 67 CG7285, CG10772, CG B

2A, SSTRl, HTRIA, FY 51, 3350, 2534, 1434 11621, CG7285,CG74

N, CSE1L, TYK2, JUND , 7297, 3727, 3726, 1 85,CG7524,CG13281

, JUNB , METAP2 , JUN 0988, 3725 ,CG1594,CG2275,CG

2275,CG4008,CG227

O

Apsor CYP24A1 1591 CG6042 B aptiganel JUN 3725 CG2275 B

Aralen NUP214, JUND, ABCB1 8021, 3727, 5243, 37 CG3820,CG2275,CG3 O

, JUNB, JUN, PLAT 26, 3725, 5327 879, CG2275, CG2275

, CG13744

arctiin CCND1 595 CG9096 B

Arecoline CDC2 983 CG5363 B

Areether CYP3A4 1576 CG9438 O argatroban SERPINC1 462 CG9456 B aripiprazole HTRIA, CYP3A4 3350, 1576 CG7485, CG9438 O

Armor NPDC1 56654 CG30420 B

Artein CDK2 , LPA, PLAT , CCN 1017, 4018, 5327, 89 CG5363, CG13744, CG O

D3, ABCB1, CCND1, JU 6, 5243, 595, 3725, 8 13744, CG9096,CG38

N, CYP4F2, CYP3A4 529, 1576 79,CG9096,CG2275,

CG3466, CG9438

ASTA CNOT6, SERPINB6, CY 57472, 5269, 1593 CG31137,CG9456,CG B

P27A1 6042 astatine HSPA4,MAPT, PLAT, S 3308, 4137, 5327, 65 CG6603, CG31057, CG O

LC5A5 28 13744, CG32669

Astemizole CYP3A4 1576 CG9438 O atazanavir CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O

Atorel HTRIA, SSTR4, SSTRl 3350, 6754, 6751 CG7485,CG7285,CG7 B

285

atorvastatin RACl , CYP3A4 , SERPI 5879, 1576, 462, 372 CG2248,CG9438,CG9 O

NCI , JUN, CSE1L, ABC 5, 1434, 5243, 3726, 456,CG2275,CG1328

Bl, JUNB, JUND, PLAT 3727, 5327 1,CG3879,CG2275,C

G2275, CG13744 Atosil ABCBl 5243 CG3879 O

Atovaquone CYP3A4 1576 CG9438 O

ATRA PLAT, CCNB1, ΡΑΧβ,Μ 5327, 891, 5080, 413 CG13744,CG3510,CG O

APT, CYP3A7, OPRK1, 7, 1551, 4986, 9611, 11186, CG31057,CG9 NCOR1 , KHDRBS1 , PSM 10657, 9861, 3315, 6 438,CG7285,CG7951 D6, HSPB1, SLC5A5,K 528, 3791, 3726, 894 ,CG4816,CG5378,CG DR, JUNB , CCND2 , MYB , 4605, 7155, 1678, 1 14207, CG32669,CG8 L2, TOP2B, TIMM8A, T 0189, 2268, 1019, 37 222,CG2275,CG9096 HOC4, GR, CDK4, JUN 27, 1593, 2249, 5708 ,CG9045,CG10223,C D,CYP27A1,FGF4,PS , 5718, 462, 5881, 58 G1728,CG1101,CG75 MD2, PSMD12, SERPIN 79, 8312, 1017, 983, 24,CG5072,CG2275, CI , RAC3 , RAC1 , AXIN 896,1103, 1021, 262 CG6042,CG4608,CG7 1,CDK2,CDC2,CCND3 6, 2247, 3725, 1386, 762,CG1100,CG9456 , CHAT, CDK6, GATA4, 324, 595, 5243, 8900 ,CG2248,CG2248,CG FGF2 , JUN, ATF2 , APC , 1579, 3082, 2254, 2 7926,CG5363,CG536 , CCNDl, ABCBl, CCNA 250, 2200, 64689, 27 3,CG9096,CG12345, 1,CYP4A11,HGF,FGF 17, 7184, 1580, 1958 CG5072,CG3992,CG4 9 , FGF5 , FBN1 , GORAS , 4311, 2257, 2220 608,CG2275,CG3042 PI, GLA, HSP90B1, CY 0,CG6193,CG9096,C P4B1 , EGR1 , MME , FGF G3879,CG3510,CG34 12, FCN2 66, CG13744, CG4608

,CG4608,CG3936,CG

7809,CG5731,CG124

2,CG9438,CG7847,C

G9565,CG4608,CG55

5

Auluton MAFB, EGR1 9935, 1958 CG10034,CG7847 O aureobasidin ABCBl 5243 CG3879 O

A

Aurothioglu- PARD6A, GORASP1 50855, 64689 CG5884, CG7809 B cose

AuTM RAC1, PARD6A 5879, 50855 CG2248, CG5884 B Axert CYP3A4 1576 CG9438 O axitinib KDR 3791 CG8222 O Axsain FOXD3 , GORASPI , PLA 27022, 64689, 5327, CG3668,CG7809,CG1 O

T , ABCBl , MAPT , FCN2 5243, 4137, 2220, 37 3744,CG3879,CG310 , JUND, JUNB, JUN, MM 27, 3726, 3725, 4311 57,CG555,CG2275,C

G2275,CG2275,CG95

65

azacyclonol CYP3A4 1576 CG9438 O Azadc CDK6, DYNLL1 , TSC1 , 1021, 8655, 7248, 52 CG5072,CG5450,CG6 B ABCB1, YN, ADAMTS1 43, 2534, 9510, 3728 147,CG3879,CG7524 , JUP,MTAP,RAC2 , 4507,5880 ,CG14869,CG11579,

CG4802, CG2248 azamulin CYP3A4 1576 CG9438 0 azanediyl ABCB1 5243 CG3879 0 group

azaspirane FGF2, JAK2 2247, 3717 CG4608, CG1594 B azelastine CYP3A4 1576 CG9438 0 azelnidipine JUNB, JUN, CYP3A4 , J 3726,3725,1576,37 CG2275, CG2275, CG9 B

UND 27 438, CG2275

azidoprazosin ABCB1 5243 CG3879 0 Aziran SER- 1992, 2324, 5092 CG9456, CG8222, CGI 0

PINB1, FLT4, PCBD1 963

Azithromycin JUN, JUND, JUNB 3725, 3727, 3726 CG2275, CG2275, CG2 B

275

Azor CYP3A4, CYP3A43 1576, 64816 CG9438, CG9438 0 Azur A MAPT 4137 CG31057 B Azure B MAPT 4137 CG31057 B BA (VAN) CYP3A4, CYP3A7 1576, 1551 CG9438, CG9438 0 Baclofen HTR1A 3350 CG7485 0 Bagren CYP3A4 1576 CG9438 0 baicalein IGF1R,CCNB1,CDK4, 3480, 891, 1019, 983 CG1842,CG3510,CG5 0

CDC2, PLAT , 5327 072,CG5363,CG1374

4

Barnidipine ABCB1 5243 CG3879 0 BAY 11-7085 CCND1,G0RASP1 595, 64689 CG9096, CG7809 B Beflavin CYP4F3, SF4 4051, 57794 CG3466, CG31550 B Benidipine ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 0 benzoyl- KDR 3791 CG8222 0 staurosporine

beraprost PLAT 5327 CG13744 0 Berbamine HSP90AA1 3320 CG1242 0 berberine ABCB1 , JUNB, BEST1 , 5243, 3726, 7439, 37 CG3879,CG2275,CG6 0

JUND, JUN, CYP3A4 27,3725,1576 264,CG2275,CG2275

, CG9438

bergamottin CYP3A4 1576 CG9438 0 bergaptol CYP3A4 1576 CG9438 0 BESTATIN CCND1 595 CG9096 B beta- ABCB1 5243 CG3879 0 citronellol

beta-eudesmol FGF2 2247 CG4608 B beta- OPRM1 4988 CG7285 B funaltrexam- ine

beta-gamma- RAC1 5879 CG2248

iminotriphosphate

bexarotene PSMD12, CCND3, CCND 5718, 896, 595 CGI 100, CG9096, CG9 B

1 096

Bezafibrate ABCB4,CYP3A4 5244,1576 CG3879, CG9438 0 BI D1870 RPS 6KA3 , RPS 6KA6 , R 6197,27330,6195,6 CG17596, CG17596, C 0

PS6KA1, RPS6KA2 196 G17596, CG17596 biapigenin CYP3A4 1576 CG9438 0 BIBF 1000 FGF2 2247 CG4608 B BIBW 22 ABCB1 5243 CG3879 0 bifeprunox HTR1A 3350 CG7485 0 Bisoprolol CYP3A4 1576 CG9438 0 Bisphenol A- CLTB 1212 CG6948 B Glycidyl

Methacrylate

bizelesin SERPINB3 6317 CG9456 B Bleomycin FGF7,TSC1,ABCB1,H 2252,7248,5243,33 CG4608 , CG6147 , CG3 0

SPA1A 03 879,CG5436

BM 41.440 PCSK7 9159 CG10772 0

BMS 310705 CYP3A4 1576 CG9438 0 BMS-262084 ABCB1 5243 CG3879 0 BMS453 CDK2 1017 CG5363 B BMS-470539 TUBB3 10381 CG3401 B BMY 7378 HTR1A 3350 CG7485 0 Borrelia- PLG 5340 CG13744 0 burgdorferi

bortezomib CYP27A1, JUND, JUN, 1593, 3727, 3725, 10 CG6042, CG2275, CG2 B

TUBAIB, HSPAIA, JUN 376, 3303, 3726, 569 275,CG1913,CG5436 B, PSMB8, PSMB5, ABC 6, 5693, 5243, 595, 1 ,CG2275,CG12323,C B1,CCND1,EIF2S1,M 965, 84061, 9531, 33 G12323,CG3879,CG9 AGT1 , BAG3 , HSPA4 , H 08, 3309, 3315, 3316 096,CG9946,CG7830 SPA5, HSPB1, HSPB2, , 3320, 64689 ,CG32130,CG6603,C HSP90AA1, GORASP1 G5436,CG14207,CG1

4207,CG1242,CG780 bosentan CYP3A4 1576 CG9438 O bosutinib CDK2 1017 CG5363 B

Bo-Xan ABCB1, IK 5243, 3550 CG3879, CG18005 B

Brefeldin A JUN, CCNB1 , JUND, HS 3725, 891, 3727, 330 CG2275,CG3510,CG2 O

PA5 , JUNB, YIF1A 9, 3726, 10897 275,CG5436,CG2275

,CG5484

bremazocine OPRK1, OPRMl 4986, 4988 CG7285, CG7285 B bryostatin JUNB, ABCB1, JUN, JU 3726, 5243, 3725, 37 CG2275,CG3879,CG2 B

ND 27 275,CG2275

Budesonide CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O bufalin CYP24A1,MYB 1591, 4602 CG6042, CG9045 B

Bumetanide BEST1 7439 CG6264 B

Bupivacaine LPA 4018 CG13744 O

Buprenorphine CYP3A4 , OPRMl , OPRK 1576, 4988, 4986 CG9438,CG7285,CG7 B

1 285

Buspirone HTR1A, CYP3A4 3350, 1576 CG7485, CG9438 O

Buthionine ABCB1 5243 CG3879 O

Buthionine SERPINB6 5269 CG9456 B

Sulfoximine

cabergoline KDR 3791 CG8222 O

CACP PCBD1, PCSK5, PPP1R 5092, 5125, 23645, 1 CG1963, CG10772, CG B

15A, ZNHIT1, JUNB, J 0467, 3726, 3725, 57 3825, CG31917, CG22

UN, KLHLl, HSPA5, PD 626, 3309, 57026, 37 75,CG2275,CG17754

XP, JUP, GORASP1, RP 28, 64689, 3921, 631 ,CG5436,CG4755,CG

SA, SERPINB3,EIF4G 7, 1981, 6591, 5269, 11579, CG7809,CG14

1, SNAI2, SERPINB6, 1958, 1965, 2321, 74 792,CG9456,CG1081

EGR1,EIF2S1,FLT1, 30, 3727, 595, 3082, 1,CG3758,CG9456,C

EZR, JUND, CCNDl, HG 1676, 3148, 1434, 33 G7847,CG9946,CG82

F, DFFA, HMGB2, CSE1 15, 3480, 3316, 3303 22, CG10701, CG2275

L,HSPB1, IGF1R,HSP , 3320, 3717 ,CG9096,CG13744,C

B2, HSPA1A, HSP90AA G8357,CG17921,CG1

1 , JAK2 3281, CG14207, CG18

42, CG14207, CG5436 ,CG1242,CG1594

Calcij ex CYP24A1,PSMD12,KS 1591, 5718, 8844, 15 CG6042,CG1100,CG2 B

Rl, CYP27B1 94 899,CG6042

Calcimycin EGR1 , JUN, CPA1 , HSP 1958, 3725, 1357, 71 CG7847, CG2275, CGI B

9 OBI , HSPA5 , HSPA4 , 84, 3309, 3308, 8655 4820,CG1242,CG543

DYNLL1 6,CG6603,CG5450 calphostin C KDR, GF13, FGF2, JU 3791,2258,2247,37 CG8222,CG4608,CG4 B ND, ADAMTS1, JUNB, J 27, 9510, 3726, 3725 608,CG2275,CG1486 UN 9, CG2275, CG2275

Calyculin EGR1 , GSK3B, ETV5 , M 1958,2932,2119,41 CG7847,CG2621,CG6 0

ΑΡΤ,ΡΡΑΙ 37,5464 892,CG31057,CG463

4

Camptothecin GSK3B, MYB, CCNA2 , R 2932,4602,890,392 CG2621, CG9045, CG3 0

PSA, HGF, MAPT, ABCB 1,3082, 4137,5243 510,CG14792,CG137 1 44, CG31057, CG3879 candesartan BEST1 7439 CG6264 B candoxatril MME 4311 CG9565 0 candoxatrilat MME 4311 CG9565 0 Canef CPB2 , CYP3A , LPA, P 1361,1576,4018,54 CG14820,CG9438, CG 0

PA1 , HGF 64,3082 13744, CG4634, CG13

744

CAPE CCND1,ABCB1 595, 5243 CG9096, CG3879 O capsanthin ABCB1 5243 CG3879 0 capsazepine PCSK7 9159 CG10772 0

Carbamazepine JUND, JUNB, CYP4F3, 3727,3726,4051,15 CG2275,CG2275,CG3 B

CYP3A4, ABCB1, JUN 76,5243,3725 466,CG9438,CG3879

, CG2275

carbamic acid FAAH, ABCB1 2166, 5243 CG6007, CG3879 0

Cardiolipins RPS 6KA3 , FOXD3 6197, 27022 CG17596, CG3668 B

Cardioplegic PIK3C2A 5286 CG11621 0 Solutions

carebastine ABCB1 5243 CG3879 0 carfentanil OPRM1 4988 CG7285 B

Carisoprodol DDX3X 1654 CG9748 0

CARNOSOL CCNB1 891 CG3510 B carvacrol JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2 B

275

carvedilol ABCB1 5243 CG3879 0

Casodex CYP4F3 , TMSB4X, EZR 4051,7114,7430 CG3466,CG4944,CG1 B

0701

caspofungin CYP3A4 1576 CG9438 0 casticin CDC2, CCNA2 983, 890 CG5363, CG3510 B catechins HGF, IK, POLS 3082, 3550, 11044 CG13744,CG18005,C B

G11265

CD 437 JUNB, HSPA5, PPP1R1 3726,3309,23645,6 CG2275,CG5436,CG3 B

5A, GORASP1, JUN, JU 4689, 3725, 3727, 10 825,CG7809,CG2275 ND, TXNIP 628 ,CG2275,CG18745

Cefotaxime CYP27A1 1593 CG6042

Ceftazidime CYP27A1 1593 CG6042

celecoxib ABCB1,PDPK1,CDK2, 5243,5170,1017,33 CG3879 , CG1210 , CG5 0

HSPA5 , CCND1 , GORAS 09, 595, 64689, 1019 363, CG5436, CG9096 PI, CDK4 ,CG7809,CG5072

Celiprolol ABCB1 5243 CG3879 0 CEP 701 CYP3A4, (JAK2) 1576, (3717) CG9438, (CG1594) 0 cephaloman- CYP3A4 1576 CG9438 0 nine

cerivastatin CYP3A4,CDK2,CSE1L 1576,1017,1434 CG9438,CG5363,CG1 0

3281

Cerulenin RPSA 3921 CG14792 0 Cetirizine ABCB1 5243 CG3879 0 Cetirizine TSC1 7248 CG6147 0 cetuximab KDR 3791 CG8222 0 CGS 26303 ECE1 1889 CG9565 0 CGS 35066 ECE1 1889 CG9565 0 CGS 35601 MME 4311 CG9565 0

Chlorampheni- CLTB 1212 CG6948 B col

chloropro- PHC2 1912 CG18414 0 caine

Chlorzoxazone CYP4F3 4051 CG3466 B chymostatin CAPN2 , CAPNS1 , FGF2 824,826,2247 CG8107,CG8107,CG4 B

608

cicaprost CCNA2 890 CG3510 B ciglitazone GORASP1 , CCND1 , UP 64689, 595, 26471 CG7809,CG9096,CG6 B

Rl 770

Ciguatoxins CYP27A1 1593 CG6042 B Cillora KLHL1 57626 CG17754 0 cilostazol CYP3A4, LPA 1576, 4018 CG9438, CG13744 0 Cimetidine ABCB1 , CYP3A4 , CYP3 5243, 1576, 1551, 40 CG3879,CG9438,CG9 B

A7, CYP4F3 51 438,CG3466

CINK4 CCND1 595 CG9096 B Cipol N HSPB1, JUNB, PDGFB, 3315, 3726, 5155, 57 CG14207,CG2275,CG B

KLHL1,NUP214, PLAT 626, 8021, 5327, 546 7103, CG17754, CG38 , PPA1 , GORASPI , JUN 4, 64689, 3727, 5479 20, CG13744, CG4634 D,PPIB,SERPINC1,C , 462, 894, 1576, 865 ,CG7809,CG2275,CG CND2 , CYP3A4 , DYNLL 5, 27022, 10105, 159 2852,CG9456,CG909 1, OXD3, PPIF, CYP2 3, 5243, 3309, 3316, 6,CG9438,CG5450,C 7A1,ABCB1,HSPA5,H 3725, 3082, 489, 547 G3668,CG2852,CG60 SPB2, JUN, HGF, ATP2 8,23462 42,CG3879,CG5436, A3, PPIA, HEY1 CG14207,CG2275,CG

13744, CG32451,CG2 852,CG11194

Ciprofloxacin CYP27A1,NF2 1593, 4771 CG6042, CG14228 B

Ciprol CIDEA 1149 CG1975 0

Cisapride CYP3A4, HTR4 1576, 3360 CG9438, CG6919 0

Citalopram CYP3A4 1576 CG9438 0

Citox CYP3A4 1576 CG9438 0

CJ-15161 OPRK1 4986 CG7285 B

Cladribine TSC1 7248 CG6147 0 clavosine B PPA1 5464 CG4634 0 clavulone II CCND1 595 CG9096 B clobazam CYP3A4 1576 CG9438 0

Clodronic BEST1 7439 CG6264 B

Acid

Clofazimine ABCB1 5243 CG3879 0 Clofibric ABCB5 , ABCB4 , CYP3A 340273, 5244, 1576 CG3879,CG3879,CG9 0 Acid 4 438

Clomipramine CYP3A4 1576 CG9438 0

Clonazepam CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 B

Clonidine MAPT, TBXAS1 4137, 6916 CG31057,CG3466 B clonidine- FOXD3 27022 CG3668 B displacing

substance

clopidogrel ABCB1 , CYP3A4 , SERP 5243, 1576, 462 CG3879,CG9438,CG9 B

INC1 456

clotiazepam CYP3A4 1576 CG9438 0 Clozapine CCND1 , PSMD12 , AXIN 595, 5718, 8312, 293 CG9096,CG1100,CG7 0

1,GSK3B,PPA1,HTR1 2, 5464, 3350, 4051, 926,CG2621,CG4634 A, CYP4F3, CYP3A4 1576 ,CG7485,CG3466,CG

9438

CMDBS 25 FGF2, FGF13 2247, 2258 CG4608, CG4608 B Co 2-1970 Pll 8909 CG2145 0 Colchicine MAPT , MAF, ABCB1 , CY 4137, 4094, 5243, 15 CG31057,CG10034,C 0

P3A4, PPIF, WNK3 76, 10105, 65267 G3879,CG9438,CG28

52, CG7177

Cordanum ABCB1 5243 CG3879 0 cornuside GORASP1 64689 CG7809 B costunolide KDR 3791 CG8222 0

Cotinine ABCB1 5243 CG3879 0

Cotrim CYP4F3 4051 CG3466 B coumarin CSEIL 1434 CG13281 0 coumarin CSEIL, CYP3A4 1434, 1576 CG13281,CG9438 0 coumarin CSEIL, CYP3A4, SERP 1434, 1576, 462 CG13281,CG9438,CG B

INC1 9456 coumermycins JAK1 3716 CG1594 B CP 31398 TSC1 7248 CG6147 0 CRA 026440 NCOR2 9612 CG7951 B CREBtide RPS6KA3 6197 CG17596 0 Crestor CYP3A4 1576 CG9438 0 Crodacid PSMD12 5718 CGllOO 0 cryptotanshi- CYP3A4 1576 CG9438 0 none

cryptoxanthin CCND1 595 CG9096 B Cyclandelate SERPINC1 462 CG9456 B cyclohexane- HTR1A 3350 CG7485 0 carboxylic

acid (2-(4- ( 2-bromo-5- methoxyben- zyl ) piperazin

-1-yl) ethyl) - (2- trifluoro- methoxy- phenyl ) amide

cyclopamine SHH, CDK2 6469, 1017 CG4637, CG5363 B cyclopiazonic CYP3A4, ATP2A2 1576, 488 CG9438, CG32451 B acid

cycloprodigi- JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2 B osin 275

cyclosporin G CYP4F3, ABCB1 4051, 5243 CG3466, CG3879 0 cyclotheona- PLAT 5327 CG13744 0 mide A

Cyproterone SERPINC1 462 CG9456 B

Acetate

Cystamine KDR, RAC1 , IK 3791, 5879, 3550 CG8222, CG2248, CGI B 8005

cytarabine JUN 3725 CG2275 B

D 21266 ABCB1 5243 CG3879 O

DA 8159 MMEL1 79258 CG9565 O

DABS CRKL 1399 CG1587 B

Dacarbazine CYP4F3 4051 CG3466 B

DADA MCRS1 10445 CG1135 B

DADSO JUND, JUNB, JUN, CYP 3727, 3726, 3725, 15 CG2275, CG2275, CG2 O

3A4 76 275,CG9438

daidzein JUNB, JUN, JUND, MET 3726, 3725, 3727, 10 CG2275, CG2275, CG2 B

AP2,MAP2 988, 4133 275,CG4008,CG3105 n

1

Dalteparin HGF 3082 CG13744 O

D-AM FOXD3 27022 CG3668 B danaproid SERPINC1 462 CG9456 B

Danazol LPA 4018 CG13744 O

Dapsone CYP4F3 4051 CG3466 B

Daral CYP3A4, CYP24A1, TS 1576, 1591, 7248, 37 CG9438,CG6042,CG6 B

CI, JUND, JUN, CYP27 27, 3725, 1593, 5154 147,CG2275,CG2275

Al, PDGFA, CYP27B1, , 1594, 3726 ,CG6042,CG7103,CG

JUNB 6042, CG2275

Darifenacin CYP4F3 4051 CG3466 B dasatinib CRKL, src, CYP3A4,N 1399, 6714, 1576, 80 CG1587, CG7524, CG9 O

UP214, ABCB1 21, 5243 438,CG3820,CG3879

DAU 6285 HTR4 3360 CG6919 O

Daunorubicin ABCB1 5243 CG3879 O dauricine ABCB1 5243 CG3879 O

Dayfen SER- 6318, 57472, 5269 CG9456, CG31137, CG B

PINB4,CNOT6,SERPI 9456

NB6

Dddd-PGD2 HSPA4, HSPAIA, HSPA 3308, 3303, 3309 CG6603, CG5436, CG5 O

5 436

decursin CCND1 595 CG9096 B

Deferoxamine JUNB,PLG,CDC2,CCN 3726, 5340, 983, 595 CG2275, CG13744, CG B

Dl, JUND, CCNA2, HGF , 3727, 890, 3082, 37 5363,CG9096,CG227

, JUN, CDK2 25, 1017 5,CG3510,CG13744,

CG2275, CG5363

DEHP ABCB1 5243 CG3879 O dehy- CYP3A4 1576 CG9438 O droaripipra- zole

Dehydroepian- GATA6 2627 CG3978 B drosterone

Sulfate

dehydroxy- ABCBl , GORASP1 , CCN 5243, 64689, 595 CG3879,CG7809,CG9 B methylepoxy- Dl 096

quinomicin

Delavirdine KLHL1,CYP3A4 57626, 1576 CG17754,CG9438 0 delp inidin JUN, DR 3725, 3791 CG2275, CG8222 0 delta-1- PPA1 5464 CG4634 0 pyrroline-5- carboxylate

delta8-THC RPS 6KA2 , JUND, CDC2 6196, 3727, 9 83, 619 CG17596,CG2275,CG 0

,RPS6KA3,RPS6KA1 7, 6195 5363, CG17596, CG17

596

Denagard CYP3A4 1576 CG9438 0 denbinobin CRKL, GORASP1 1399, 64689 CG1587, CG7809 B denosumab BEST1 7439 CG6264 B deoxyhypusine EIF5 1983 CG9177 B deoxyverruco- HSPA5 3309 CG5436 0 sidin

Depas CYP3A4, CSE1L 1576, 1434 CG9438, CG13281 0 dephosphono- PPA1 5464 CG4634 0 calyculin A

Deproceptin OPRM1 4988 CG7285 B deramciclane CYP3A4 1576 CG9438 0 dermorphin OPRM1 4988 CG7285 B desethyl- CYP3A4 1576 CG9438 0 chloroquine

desloratadine ABCBl 5243 CG3879 0 desmethylaze- CYP3A4 1576 CG9438 0 lastine

Desmethylde- CYP3A4 1576 CG9438 0 prenyl

desmethyl- CYP3A4 1576 CG9438 0 tamoxifen

DEVD-CHO MST1 4485 CG13744 0 dexecadotril MME 4311 CG9565 0 dexloxi- CYP4F3 4051 CG3466 B glumide Dextropro- CYP3A4 1576 CG9438 0 poxyphene

Diaben CYP3A4 1576 CG9438 0

Diacomit CYP3A4 1576 CG9438 0 diadenosine CDC2 983 CG5363 B tetraphos- phate

Didanosine BEST1 7439 CG6264 B dillapiol CYP3A4 1576 CG9438 0

Diltiazem PREP, CYP3A4, ABCB1 5550, 1576, 5243, 40 CG5355,CG9438,CG3 B

, CYP4F3 51 879,CG3466

Dinoprostone PSMD12,RAC1,TSC1, 5718, 5879, 7248, 37 CG1100,CG2248,CG6 0

JUND, GF9, JUN, PHC 27, 2254, 3725, 1912 147,CG2275,CG4608

2, JAK3, FGF2, VEGFC , 3718, 2247, 7424, 6 ,CG2275,CG18414,C

, C2orf3, FGF7, HGF, 936, 2252, 3082, 138 G1594,CG4608, CG71

ATF2 , MAP4K1 , BCB1 6, 11184, 5243, 595, 03,CG1965,CG4608,

, CCND1 , JUNB , EGR1 , 3726, 1958, 182 CG13744,CG30420,C

JAG1 G7097,CG3879,CG90

96,CG2275,CG7847, CG6127

Diosgenin GORASP1 64689 CG7809 B diosmetin RAC1 5879 CG2248 B dioxirane TBXAS1 6916 CG3466 B

Dioxolan RAC1 5879 CG2248 B

Dipyrone CYP4F3, CYP3A4 4051, 1576 CG3466, CG9438 0

Disopyramide MAF, PPA1, PREP 4094, 5464, 5550 CG10034,CG4634,CG 0

5355

Ditiocarb HSPA1B, HSPA2 3304, 3306 CG31449,CG5436 0

Dizocilpine TSC1, HTR1A, CCND1 7248, 3350, 595 CG6147, CG7485, CG9 B

Maleate 096

DNSC1 CYP3A4, SERPINC1 1576, 462 CG9438, CG9456 B

Doca EGR1 1958 CG7847 0 dofequidar ABCB1 5243 CG3879 0

Dolomin CSE1L 1434 CG13281 0

Domperidone ABCB1 5243 CG3879 0

Doxazosin HTR1A 3350 CG7485 0 doxifluridine STUB1 10273 CG5203 B

Doxycycline NOTCH1, MYB, JUN, CY 4851, 4602, 3725, 15 CG3936, CG9045, CG2 B

P3A4, FGF7 76, 2252 275,CG9438,CG4608

DPC 681 CYP3A4 1576 CG9438 0 DPCPX CPA1 1357 CG14820 B

DPPH JAG1 182 CG6127 O

Droxia JUN,ABCB1,CYP3A4, 3725, 5243, 1576, 27 CG2275,CG3879,CG9 B

FOXD3, CDC2 022, 983 438,CG3668,CG5363

Drysol MAPT 4137 CG31057 B duloxetine MAPT 4137 CG31057 B

Durapatite JAK1, PPA1 3716, 5464 CG1594, CG4634 O

Dursbanoxon CYP3A4 1576 CG9438 O

DX 9065a HGF 3082 CG13744 O

Dxms PLAT, RPSA, SLC5A5, 5327, 3921, 6528, 37 CG13744,CG14792,C B

JUNB, JUND, FGF2 , MB 26, 3727, 2247, 4153 G32669,CG2275,CG2

L2,MME,TSC1,CYP4Z , 4311, 7248, 199974 275,CG4608,CG7763

1,HSPB2,HSPB8,FGF , 3316, 26353, 2252, ,CG9565,CG6147,CG

7,VEGFC,CCND1,CHA 7424, 595, 1103, 524 3466, CG14207, CG14

T,ABCB1,CYP4A11,C 3, 1579, 1576, 84061 207,CG4608,CG7103

YP3A4 , MAGT1 , TXNIP , 10628, 896, 891, 15 ,CG9096,CG12345,C

, CCND3, CCNB1, CYP2 93, 5708, 8313, 3082 G3879,CG3466,CG94

7A1,PSMD2,AXIN2,H , 3320, 3725, 126393 38,CG7830,CG18745

GF,HSP90AA1, JUN,H ,64689 ,CG9096,CG3510,CG

SPB6, GORASP1 6042,CG7762,CG792

6,CG13744,CG1242, CG2275,CG4183,CG7 809

dynapen ABCB1 5243 CG3879 O

Dynatra RASA3 , SSTR4 , MAPT, 22821, 6754, 4137, 1 CG6721,CG7285,CG3 B

SER- 992, 6916, 27022, 10 1057,CG9456,CG346

PINB1,TBXAS1, FOXD 988, 84062, 1357, 33 6,CG3668,CG4008,C

3,METAP2, DTN1,CPA 50, 3308, 4133, 5464 G6856,CG14820,CG7

1,HTR1A,HSPA4,MAP , 6751, 4988, 4771 485,CG6603,CG3105

2,PPA1,SSTR1,0PRM 7,CG4634,CG7285,C

1,NF2 G7285, CG14228 dynorphin OPRK1 4986 CG7285 B dysidenin OPRK1 4986 CG7285 B dysprosium SLC5A5 6528 CG32669 O dystrobrevin MAPT 4137 CG31057 B

E 10 MAF, CCND1 4094, 595 CG10034,CG9096 B

EACA PLG, SERPINC1 5340, 462 CG13744,CG9456 O ebastine SERPINC1 462 CG9456 B ebrotidine CYP4F3 4051 CG3466 B

Econ PDPK1,CYP4F2, FYN, 5170, 8529, 2534, 35 CG1210,CG3466,CG7 B IK, PCSK7 50, 9159 524,CG18005,CG107

72

econazole PCSK7 9159 CG10772 O ecteinascidin CYP3A4, ABCBl, CYP4 1576, 5243, 4051 CG9438,CG3879,CG3 O

743 F3 466

ectoine CYP4F3 4051 CG3466 B

Edex MME , ATPIB1 , PDGFB, 4311, 481, 5155, 126 CG9565,CG9258,CG7 O

CNGA2 , PLAT 0, 5327 103, CG7779, CG1374

Edrophonium PLAT 5327 CG13744 O efavirenz ABCBl , MAPT , KLHL1 , 5243, 4137, 57626, 4 CG3879, CG31057, CG B

CYP4F3, CYP3A4 051, 1576 17754, CG3466,CG94

38

efrapeptin CYP3A4 1576 CG9438 O

EGCg FGF1, HSPA5, IGF1R, 2246,3309,3480,10 CG4608,CG5436,CG1 B

CDK2 , RPSA, JUND, FG 17, 3921, 3727, 2247 842,CG5363,CG1479

F2, ABCBl, HSPA4, JU , 5243, 3308, 3725, 3 2,CG2275,CG4608,C

N, JUNB, HGF 726,3082 G3879,CG6603,CG22

75, CG2275, CG13744

EGRck HGF 3082 CG13744 O

EHT 1864 PLAT 5327 CG13744 O eletriptan RAC1 5879 CG2248 B

Embelin CYP3A4 1576 CG9438 O embellistatin GORASP1 64689 CG7809 B

EMD 53998 FGF2 2247 CG4608 B

EMD 61753 TNC 3371 CG5550 O emetine OPRK1 4986 CG7285 B

E-MIX 80 CCND1 595 CG9096 B

Emodin CCND1 , JUND, RAC1 , K 595, 3727, 5879, 379 CG9096,CG2275,CG2 B

DR, GORASP1 , JUN, JU 1, 64689, 3725, 3726 248,CG8222,CG7809

NB , CG2275, CG2275

Empecid CYP3A4 , CYP3A7 , THO 1576, 1551, 10189 CG9438,CG9438,CG1 O

C4 101

emtricitabine THOC4 10189 CG1101 B enadoline KLHL1 57626 CG17754 O

Enalapril KLHL1, PLAT 57626, 5327 CG17754,CG13744 O

Enalaprilat PLAT 5327 CG13744 O

Enediynes PLAT 5327 CG13744 O

Enelone CCNA2 890 CG3510 B

Enoximone ATF2 1386 CG30420 B EPIB MME 4311 CG9565 0

Epicar CYP4A11 1579 CG3466 B epicatechin SERPINB3 6317 CG9456 B gallate

epimedin C CCND1 595 CG9096 B

Epoprostenol SER- 462, 5879, 1576, 227 CG9456, CG2248, CG9 0

PINC1 , RAC1 , CYP3A4 7,2246 438,CG7103,CG4608

, FIGF, GF1

Epostane FGF1 2246 CG4608 B

Epothilones FOXD3 27022 CG3668 B epoxyberga- ABCB1 5243 CG3879 0 mottin

epsilon- CYP3A4 1576 CG9438

viniferin

eptifibatide CYP4F3 4051 CG3466 B ergotamine PLAT 5327 CG13744 0 eriocalyxin B HTR1A 3350 CG7485 0 erlotinib CCND1, ABCB1, JAK2, 595,5243,3717,157 CG9096, CG3879, CGI B

CYP3A4 6 594,CG9438

erucin CYP3A4 1576 CG9438 0 Eryc JUN, CYP3A4 , ABCB1 , 3725,1576,5243,30 CG2275, CG9438 , CG3 0

HGF, JUND, PPAl , JUN 82, 3727, 5464, 3726 879 , CGI 3744 , CG227 B 5, CG4634, CG2275

Eskazine EGR1 , MAPT 1958,4137 CG7847, CG31057 0

Estramustine MAPT 4137 CG31057 B

ET18-0me MAPT 4137 CG31057 B

Etfc cpd PCSK7 9159 CG10772 0

Ethacrynic CYP3A4 1576 CG9438 0

Acid

Ethambutol GORASP1 64689 CG7809 B Etidronic ABCB1 5243 CG3879 0 Acid

Etodolac SER- 6317,891,1019,224 CG9456, CG3510 , CG5 B

PINB3,CCNB1,CDK4, 7,890,983,1017 072 , CG4608 , CG3510 FGF2,CCNA2,CDC2,C ,CG5363,CG5363 DK2

Etoposide TOP2A, JUND, ABCB1 , 7153,3727,5243,37 CG10223, CG2275, CG B

JUNB, SF4, JUN 26,57794,3725 3879, CG2275, CG315

50, CG2275

etoricoxib JUN 3725 CG2275 B Etorphine CYP3A4 1576 CG9438 O etravirine OPRM1 4988 CG7285 B Eufor CYP4F3,CYP3A4,HTR 4051,1576,3350 CG3466,CG9438,CG7 O

1A 485

eumelanin HTR1A 3350 CG7485 O eupatilin CCND1,CCNB1,CDK2 595,891,1017 CG9096,CG3510,CG5 B

363

everolimus CDK2 1017 CG5363 B Evex CCNB1,N0TCH1, TSC1 891, 4851, 7248, 961 CG3510,CG3936,CG6 O

, COR1 , COR2 , QRSL 1, 9612, 55278, 3727 147,CG7951,CG7951 1, JUND, PLAT, PLG, J , 5327, 5340, 3726, 3 ,CG6007,CG2275,CG UNB, HSPA5, JAG1, JU 309, 182, 3725, 4292 13744, CG13744,CG2 N, MLH1 , TBXAS1 , KDR , 6916, 3791, 4137, 1 275,CG5436,CG6127 , MAPT , EGR1 , YES1 , I 958, 7525, 3480, 159 ,CG2275,CG11482,C GF1R, CYP27B1, EGR3 4, 1960, 6752, 7430, G3466,CG8222,CG31 , SSTR2, EZR, SERPIN 462, 6469, 6591, 392 057,CG7847,CG7524 CI, SHH, SNAI2, RPSA 1, 6434, 6751, 1576, ,CG1842,CG6042,CG ,SFRS10,SSTR1,CYP 7439, 2932, 4899, 40 7847, CG7285, CG107 3A4,BEST1,GSK3B,N 51, 10521, 7114, 524 01,CG9456,CG4637, RF1,CYP4F3, DDX17, 3, 4478, 2200, 9352, CG3758, CG14792, CG TMSB4X, ABCB1 , MSN, 2258, 1017, 983, 659 10128, CG7285,CG94 FBN1, TXNL1, FGF13, 7, 595, 1357, 1593, 9 38,CG6264,CG2621, CDK2 , CDC2 , SMARCA4 01, 2626, 3146, 3303 CG3114,CG3466,CG1 ,CCND1,CPA1,CYP27 , 2254, 3082, 3316, 2 0279,CG4944,CG387 Al , CCNG2 , GATA4 , HM 6353, 25800, 1019, 2 9,CG10701,CG3936, GB1,HSPA1A, FGF9 , H 249, 2252, 890, 2247 CG5495,CG4608,CG5 GF, HSPB2, HSPB8, SL , 27022, 5045, 3315 363,CG5363,CG5942 C39A6,CDK4,FGF4,F ,CG9096,CG14820,C GF7,CCNA2,FGF2,FO G6042,CG11525,CG3 XD3, FURIN, HSPB1 992,CG17921,CG543

6,CG4608,CG13744,

CG14207,CG14207,C

G6817,CG5072,CG46

08,CG4608,CG3510,

CG4608,CG3668,CG1

0772, CG14207

Evodin HSPB1 3315 CG14207 B exenati CCND1, TXNIP, JAK1, 595, 10628, 3716, 19 CG9096, CG18745, CG B

EGR1 58 1594, CG7847

Extina CYP4F3,KSR1,ABCB1 4051, 8844,5243, 89 CG3466,CG2899,CG3 O ,CCND3,CYP3A4,CYP 6, 1576, 8529 879,CG9096,CG9438

4F2 ,CG3466

ezetimibe CYP4F2 8529 CG3466 B

F 11440 ABCB1 5243 CG3879 0

Fanchinine GORASP1 , ABCB1 , CCN 64689, 5243, 595, 22 CG7809,CG3879,CG9 B

Dl, FGF2 47 096,CG4608

F-Ara-A HTR1A 3350 CG7485 0 febuxostat CYP3A5, CYP4F3, 1577, 4051, (2247) CG3466, CG3466, (CG B

(FGF2) 4608) felbamate CYP4F3 4051 CG3466 B

Felodipine ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 0 fenitrothion CYP3A4 1576 CG9438 0 fenofibric CYP3A4, CYP4A11 1576, 1579 CG9438, CG3466 0 acid

Fenoprofen SLC5A8, (CYP4A11) 160728, (1579) CG8451, (CG3466) B

Fenretinide TUBB3,SF4, JAK1,EI 10381, 57794, 3716, CG3401, CG31550, CG 0

F2S1, JUN, PLAT, CCN 1965, 3725, 5327, 59 1594,CG9946,CG227

Dl 5 5,CG13744,CG9096 fexofenadine CCND1 595 CG9096 B fingolimod ABCB1 5243 CG3879 0 fipronil JAK3 3718 CG1594 B fisetin CDK6, CDK4, GORASP1 1021, 1019, 64689 CG5072,CG5702,CG7 0

809

FLCZ CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 0

Flecainide ABCB1 5243 CG3879 0

Flesinoxan PREP 5550 CG5355 0 flibanserin HTR1A 3350 CG7485 0

Floxacillin CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 0

Fludeoxyglu- ABCB1 5243 CG3879 0 cose F 18

Flunarizine JAG1 182 CG6127 0 fluorexon ABCB1 5243 CG3879 0

Fluorouracil PCSK7,MLH1, TXNIP, 9159, 4292, 10628, 7 CG10772,CG11482,C 0

BEST1,WNK1, TBXAS1 439, 65125, 6916, 89 G18745,CG6264,CG7

, CCNA2, CPA1, ABCB1 0, 1357, 5243, 1958, 177,CG3466,CG3510

,EGR1,FGF7,HSPA4, 2252, 3308, 1434, 64 ,CG14820,CG3879,C

CSE1L, GORASP1 689 G7847,CG4608,CG66

03, CG13281, CG7809

Fluparoxan GORASP1 64689 CG7809 B

Flupenthixol HTR1A 3350 CG7485 0 fluvoxamme ABCB1 , CYP3A4 , HTR1 5243, 1576, 3350 CG3879,CG9438,CG7 O A 485

fondaparinux HTR1A 3350 CG7485 O Fonofos SERPINC1 462 CG9456 B Format CYP3A4 1576 CG9438 O Forskolin TUBB3 , PLAT , PAX6 , 10381, 5327, 5080, 2 CG3401, CG13744, CG O

GF7,CYP27B1,SLC5A 252, 1594, 6528, 912 11186, CG4608,CG60 5,PRPF4,ATP1B1,0P 8, 481, 4987, 4478, 3 42, CG32669, CG6322 RL1 , MSN, HMGB1 , PDG 146, 5155, 4137, 675 ,CG9258,CG7285,CG FB, MAPT , SSTR1 , JUN 1, 3725, 491,4988,5 10701, CG17921,CG7 , ATP2B2 , OPRM1 , ABC 243, 595, 1103, 2627 103,CG31057,CG728 Bl, CCND1, CHAT, GAT , 170690, 1958, 2247 5,CG2275,CG2198,C A6 , ADAMTS 16 , EGR1 , , 2324, 1576, 3350, 3 G7285,CG3879,CG90 FGF2, FLT4,CYP3A4, 082 96, CG12345, CG3978 HTR1A, HGF ,CG14869,CG7847,C

G4608,CG8222,CG94

38,CG7485,CG13744 fosamprenavir HGF 3082 CG13744 O Foscarnet CYP3A4 1576 CG9438 O Frakefamide PPA1 5464 CG4634 O fucoidan KDR, FGF2 , HGF, SERP 3791, 2247, 3082, 46 CG8222,CG4608,CG1 B

INCI, PLG 2, 5340 3744,CG9456,CG137

44

fulvestrant JUN, CCND2 , ATF2 , CC 3725, 894, 1386, 595 CG2275,CG9096,CG3 B

ND1 0420, CG9096

Fura-2 ABCB1,PCSK7 5243, 9159 CG3879, CG10772 O furafylline CYP3A4,FURIN 1576, 5045 CG9438, CG10772 O Furylfuramide FURIN 5045 CG10772 O FYDE PREP,Xl,FOXD3,GOR 5550, 7494, 27022, 6 CG5355,CG9415,CG3 B

ASP1, JUN, PDXP,MAP 4689, 3725, 57026, 4 668,CG7809,CG2275

T 137 ,CG4755,CG31057

Gambogic acid CDC2,KDR 983, 3791 CG5363, CG8222 B gedunin KDR 3791 CG8222 O gefitinib CYP3A4, (HSP90AA1) 1576, (3320) (CG1242) , CG9438 O

Geldanamycin HSPA4 , HSPA2 , HSPA1 3308,3306,3304,33 CG6603,CG5436,CG3 B

B,HSPA5,STUB1,HSP 09, 10273, 3315, 372 1449,CG5436,CG520 Bl, JUN,RAC1,CCNB1 5,5879, 891, 595, 90 3,CG14207,CG2275, , CCND1, CCNT1, FGF2 4,2247, 983, 1017,3 CG2248,CG3510,CG9 ,CDC2,CDK2,HGF,HS 082, 3320, 11140, 33 096,CG6292,CG4608 P90AA1 , CDC37 , HSPA 03 ,CG5363,CG5363,CG 1A 13744, CG1242,CG12

019,CG5436

Gemfibrozil CYP3A4, PLG, JUNB, S 1576, 5340, 3726, 10 CG9438, CG13744, CG B

LC22A7, JUN, JUND 864,3725,3727 2275,CG8654,CG227

5,CG2275

genipin JU D 3727 CG2275 B Gentamicins JUN 3725 CG2275 B gepirone CYP3A4, HTR1A 1576, 3350 CG9438, CG7485 0 Gestodene HTR1A 3350 CG7485 0 GF 120918 CYP3A4 , ABCBl , KLHL 1576, 5243, 57626 CG9438,CG3879,CG1 0

1 7754

GGTI 298 KLHL1 57626 CG17754 0

GI 129471 CDK2 1017 CG5363 B

Ginkgo- JUND, CYP3A4 , CYP4F 3727, 1576, 4051, 37 CG2275,CG9438,CG3 0 biloba- 3, JUNB, JUN, PLAT, C 26, 3725, 5327, 1594 466, CG2275, CG2275 extract YP27B1 , CG13744, CG6042 glabridin CYP27B1 1594 CG6042 B

GLCa SERPINC1, EXT1 462, 2131 CG9456, CG10117 B

Glumin THOC4,MSN, HSP90AA 10189, 4478, 3320, 3 CG1101, CG10701, CG B

1, DNAJB1, HSPA8 337, 3312 1242, CG10578, CG31

449

Glycyron JUND, KLHL1, HMGB1, 3727, 57626, 3146, 3 CG2275, CG17754, CG B

JUNB, JUN, GORASP1 726,3725,64689 17921, CG2275,CG22

75, CG7809

glyox GORASP1 64689 CG7809 B

Gnidimacrin CYP27B1 1594 CG6042 B gossypetin CDK2 1017 CG5363 B gossypol AGL,CCND1,G0RASP1 178,595,64689 CG9485,CG9096,CG7 B

809

GR 113808 GORASP1 64689 CG7809 B grifolin CCND1,CDK4 595,1019 CG9096, CG5072 B

Grofo CYP4F3, CYP3A4, ABC 4051,1576,5243 CG3466,CG9438,CG3 0

Bl 879

Guggulsterone ABCBl, CCND1 5243,595 CG3879, CG9096 0 gusperimus HSPA8 , HSP90AA1 3312,3320 CG31449, CG1242 B

Harzol CCNB1 , TUBA1B, MAP2 891,10376,4133, CG3510,CG1913,CG3 B

,CDC2 3 1057, CG5363

Hbim OPRL1 , KDR 4987,3791 CG7285, CG8222 B

HESPERETIN KDR 3791 CG8222 0

Hexadime- CDK4 1019 CG5072 0 thrine

HMBA SERPINC1 462 CG9456 B hypsiziprenol FGF4 2249 CG4608 B

A9

hypusine CCND1 595 CG9096 B hyrtio- EIF5 1983 CG9177 B erectine A

ibandronic EYA1 2138 CG9554 0 acid

IBMX JAK3 , MME , HGF, LPA 3718, 4311, 3082, 40 CG1594,CG9565,CG1 0

18 3744, CG13744

I-BOP CCND1,EYA1 595, 2138 CG9096, CG9554 B

Ibotenic Acid LPA 4018 CG13744 0

Icosapent PLAT 5327 CG13744 0

ICRF 193 POLS 11044 CG11265 B idebenone TOP2B 7155 CG10223 B

IDN 5390 HSPA4 3308 CG6603 0

I fosfamide TUBB3 10381 CG3401 B

I fosfamide CYP4F3 4051 CG3466 B

IGF-1 CYP3A4 1576 CG9438 0

Iloprost RBM6, RAC1 10180,5879 CG4887, CG2248 B imatinib CYP3A4,EGR1, JUN,C 1576, 1958, 3725, 59 CG9438,CG7847,CG2 B

CND1, PDGFB, CCND2, 5, 5155, 894, 890, 37 275,CG9096,CG7103

CCNA2 , KIF5B, PCSK7 99, 9159, 3717, 3726 ,CG9096,CG3510,CG

, JAK2 , JUNB, KDR, HS , 3791, 3308, 5243, 2 7765, CG10772, CG15

PA4, ABCB1, FGF2, CD 247,1017, 1399, 308 94, CG2275, CG8222,

K2, CRKL, HGF 2 CG6603,CG3879,CG4

608,CG5363,CG1587

, CG13744

imidafenacin ABCB1 5243 CG3879 0 imperatorin CYP3A4 1576 CG9438 0

Impulsin CCND1 595 CG9096 B

Imrecoxib FAAH 2166 CG6007 B

Imutex HIST2H3C,MAPT,HIS 126961, 4137, 8352, CG5825, CG31057, CG B

T1H3C,BEST1,CYP3A 7439, 1551, 8353, 40 5825,CG6264,CG943

7,HIST1H3E,CYP4F3 51 8,CG5825,CG3466 indazole CYP4F3 4051 CG3466 B

Indinavir CYP4F3, CYP3A4, ABC 4051, 1576, 5243 CG3466,CG9438,CG3 0

Bl 879

indiplon ABCB1 5243 CG3879 0 indirubin-3 ' - CYP3A4 1576 CG9438 O monoxime

infliximab KDR, PSMD12 3791, 5718 CG8222, CGllOO O inogatran PSMD12 5718 CGllOO O

Ipral CPB2 1361 CG14820 B

Iprivask ABCB1 5243 CG3879 O ipsapirone PLG 5340 CG13744 O irbesartan JUNB, JUND, JUN, BES 3726, 3727, 3725, 74 CG2275, CG2275,CG2 B

Tl 39 275, CG6264

Iressa RACl , HGF, CCNDl, CY 5879, 3082, 595, 157 CG2248, CG13744, CG O

P3A4, IGF1R 6,3480 9096,CG9438,CG184 irinotecan PCSK7,CDC2,CYP3A4 9159, 983, 1576, 576 CGI 0772, CG5363, CG O

, KLHL1, ABCB1 26, 5243 9438, CG17754, CG38

79

irisolidone JUNB, JUND, JUN 3726, 3727, 3725 CG2275,CG2275,CG2 B

275

irofulven JUN 3725 CG2275 B

Irox EIF5B 9669 CG10840 O

I smo PHC2 1912 CG18414 O

I sobac CSE1L 1434 CG13281 O isochaihulacCYP3A4 1576 CG9438 O tone

I sodonol EGR1 1958 CG7847 O isoflavone IGF1R 3480 CG1842 O

I sorhamnetin BEST1 7439 CG6264 B isosteviol ABCB1 5243 CG3879 O

I sradipine POLS 11044 CG11265 B

I stidina CYP3A4 1576 CG9438 O

ITF 2357 ABCB1 5243 CG3879 O

Itraconazole ABCB1,CYP3A4,CYP4 5243, 1576,4051 CG3879,CG9438,CG3 O

F3 466

Ivermectin KLHL1, ABCB1 57626, 5243 CG17754,CG3879 O ixabepilone ABCB1 5243 CG3879 O

J 113397 CYP3A4 1576 CG9438 O

J 113397 OPRL1 4987 CG7285 B j asplakino- JUN, JUNB, JUND 3725, 3726, 3727 CG2275,CG2275,CG2 B lide 275

j uglone JUND 3727 CG2275 B j uzentaihoto MAPT 4137 CG31057 B K 252 CDC2, PPA1 983, 5464 CG5363, CG4634 B kaempferol CYP3A4, JAK3, AAH, 1576, 3718, 2166, 37 CG9438,CG1594,CG6 B

JUND, JUN, IK, JUNB 27, 3725, 3550, 3726 007,CG2275,CG2275

,CG18005,CG2275

KAFA JUNB 3726 CG2275 B kah eol CYP4F3 4051 CG3466 B

Kainic MAP2 , METAP2 , JUN 4133, 10988, 3725 CG31057,CG4008,CG B

2275

kami-untan-to JUN 3725 CG2275 B

Kaolin SERPINC1,PLG 462, 5340 CG9456, CG13744 B

KB 2796 PLG 5340 CG13744 O K-DR PPA1 5464 CG4634 O Keloid ABCB1 5243 CG3879 O Kemi EGR1, PREP,NF2 1958, 5550, 4771 CG7847,CG5355,CG1 O

4228

ketazocine NF2 4771 CG14228 B Keto- OPRK1 4986 CG7285 B pgflalpha

KKHA-761 SERPINC1 462 CG9456 B KN 62 HTR1A 3350 CG7485 O KN 93 NOTCH1, CDK4 4851, 1019 CG3936, CG5072 B KNK 437 HSPAIA, HSPB2, HSPB 3303, 3316, 3315, 33 CG5436, CG14207, CG B

1,HSPA4 08 14207, CG6603

KP372-1 HSPA4 3308 CG6603 O K-PAM CSE1L, HRB, SERPINC 1434, 3267, 462 CG13281,CG3365,CG B

1 9456

KPMK PDPK1 5170 CG1210 B KR 31831 GORASP1 64689 CG7809 B KRM 1648 KDR 3791 CG8222 O K-SR PPP2CA, GSK3B, GTF3 5515, 2932, 2975 CG7109,CG2621,CG7 B

CI 099

kurarinone CYP3A4 1576 CG9438 O

KYNA KDR 3791 CG8222 O

L 685458 NOTCH1, HEY1 4851, 23462 CG3936, CG11194 B

L797591 CYP3A4 1576 CG9438 O

LAGA SSTR1 6751 CG7285 B

Lamivudine CSE1L, KLHL1 1434, 57626 CG13281,CG17754 O lamotrigine KLHL1 57626 CG17754 O lanreotide HTR1A 3350 CG7485 O lapachenole PPA1 5464 CG4634 O lapatinib CYP3A4 1576 CG9438 O

LAQ824 TUBA1B, HSP90AA1 10376,3320 CG1913, CG1242 B laquinimod HSP90AA1 3320 CG1242 O latrunculin A TMSB4X, PCBD1 7114, 5092 CG4944, CG1963 O

LBH589 TUBA1B, HSP90AA1 10376,3320 CG1913, CG1242 B leflunomide PDPK1, YN 5170, 2534 CG1210, CG7524 B lenalidomide JU D, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2 B

275

Lendorm JUN 3725 CG2275 B

Lentinan CYP3A4 1576 CG9438 O

Leukotriene JUNB, PLCB2, JUN, JU 3726, 5330, 3725, 37 CG2275,CG3620,CG2 B

B4 ND 27 275,CG2275

Leukotriene JUN, ABCB5 , KLHL1 , J 3725, 340273, 57626 CG2275,CG3879,CG1 B

C4 UND, JUNB , 3727, 3726 7754, CG2275, CG227 o

Leukotriene JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2 B

D4 275

leukotrienes HTR1A, SSTR4, SSTR1 3350, 6754, 6751 CG7485,CG7285,CG7 B

285

Levonorgestre PLAT, PLG, JUN, CSE1 5327, 5340, 3725, 14 CG13744,CG13744,C B

1 L 34 G2275, CG13281 liarozole CSE1L 1434 CG13281 O lintopride HTR4, (CYP3A4) 3360, (1576) CG6919, (CG9438) O liquiritin HTR4 3360 CG6919 O

LMWH HSPB2 , PLAT , MAPT , H 3316, 5327, 4137, 33 CG14207,CG13744,C B

SP90AA1,HSPB1,PPI 20, 3315, 5479, 462, G31057,CG1242,CG1

B, SERPINC1, JUN, JU 3725, 3726, 3727, 30 4207,CG2852,CG945

NB, JUND, HGF, CDK2, 82, 1017, 5340, 2931 6,CG2275,CG2275,C

PLG, GSK3A, ADAMTS5 , 11096, 2324, 2247, G2275,CG13744,CG5

, LT4, GF2, DDX5 , R 1655, 3921, 595, 646 363,CG13744,CG262

PSA, CCND1 , GORASP1 89, 2258, 2246, 2252 1,CG14869,CG8222,

, FGF13, FGF1, FGF7, , 26281, 1361, 1593 CG4608, CG10279, CG

FGF20,CPB2,CYP27A 14792, CG9096,CG78

1 09,CG4608,CG4608,

CG4608,CG4608,CG1

4820, CG6042

LNAC HSPA5,CCND2, JUND, 3309, 894, 3727, 308 CG5436,CG9096,CG2 B

HGF, ABCB1, JUN, PDP 2, 5243, 3725, 5170, 275,CG13744,CG387

Kl, HSPA4, HSPAIA, J 3308,3303,3726, 64 9,CG2275,CG1210,C

UNB, GORASP1 689 G6603,CG5436,CG22 75, CG7809 lonafarnib GORASP1 64689 CG7809 B lonidamine ABCB1 5243 CG3879 O

Loperamide CYP3A4 , ABCB1 , OPRM 1576, 5243, 4988 CG9438,CG3879,CG7 O

1 285

lopinavir ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 O

Lopril PLAT, PLG 5327, 5340 CG13744,CG13744 O

Loratadine ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 O

Lorazepam CYP3A4 1576 CG9438 O

Lorex CPA1 1357 CG14820 B

Losartan SLC22A12, CYP27B1, 116085, 1594, 4153, CG8654,CG6042,CG7 B

MBL2, CYP3A4 1576 763,CG9438

Lovan SMARCA4 , PLG, SMARC 6597, 5340, 6595 CG5942, CG13744, CG O

A2 5942 loxiglumide SMARCA2 6595 CG5942 B

L-T3 IK, CYP3A4 3550, 1576 CG18005,CG9438 B lupeol PPA1 5464 CG4634 O luteolin JUND, CYP3A4 , IGF1R 3727, 1576, 3480, 59 CG2275,CG9438,CG1 B

, CCNDl, HGF, JUN, JU 5, 3082, 3725, 3726 842,CG9096,CG1374

NB 4,CG2275,CG2275 lutetium JUNB 3726 CG2275 B

Lutex SLC19A1, JUN,MAP2, 6573, 3725, 4133, 10 CG14694,CG2275,CG O

METAP2, HSPB1, FAAH 988,3315,2166,983 31057, CG4008,CG14

, CDC2, PDGFB, PREP, , 5155, 5550, 1017, 4 207,CG6007,CG5363

CDK2, SERPINC1,RPS 62, 3921, 5243, 595, ,CG7103,CG5355,CG

A,ABCB1,CCND1,EIF 1978, 4137, 1576, 64 5363,CG9456,CG147

4E1,MAPT,CYP3A4,G 689,3082,3316,195 92,CG3879,CG9096,

ORASP1, HGF, HSPB2, 9, 2252 CG8846, CG31057, CG

EGR2, FGF7 9438,CG7809,CG137

44, CG14207, CG7847

, CG4608

LY 117018 FGF7 2252 CG4608 B

LY 293111 CCNA2,CDK2 890, 1017 CG3510, CG5363 B

LY 293284 CDK2 1017 CG5363 B

LY 303511 HTR1A 3350 CG7485 O

LY231514 EGR1 1958 CG7847 O mahanine TBXAS1 6916 CG3466 B

Maleimides CCNDl 595 CG9096 B

Malix GSK3A 2931 CG2621 B manzamine A CYP3A4 1576 CG9438 O maraviroc GSK3A 2931 CG2621 B

MBC1 CYP3A4 1576 CG9438 0

MCYST-LR PPA1, PPP2CA 5464, 5515 CG4634, CG7109 0

Mebumal PPP2CA 5515 CG7109 0

Medemycin ATP2B2 491 CG2191 0

MedroxyproCYP3A4, SERPINC1,M 1576, 462, 4478, 372 CG9438, CG9456, CGI B gesterone 17- SN, JUN 5 0701, CG2275

Acetate

Melatol CCND1, JUN, MAPT, CY 595, 3725, 4137, 405 CG9096,CG2275,CG3 B

P4F3, OXD3 1, 27022 1057,CG3466,CG366 o

meletin JUNB, JUN, HSPB2, CC 3726, 3725,3316, 89 CG2275, CG2275, CGI B

NB1, GSK3B, TSC1, PL 1, 2932, 7248, 5327, 4207, CG3510, CG262

AT,ABCB1,CYP3A4,H 5243, 1576, 3315, 98 1,CG6147,CG13744,

SPBl, CDC2, JUND, HS 3, 3727, 3308, 3303, CG3879,CG9438,CG1

PA4,HSPA1A,CDK2,H 1017, 3320 4207,CG5363,CG227

SP90AA1 5,CG6603,CG5436,C

G5363,CG1242 melitten PLAT, RAC1 5327, 5879 CG13744,CG2248 0 meloxicam RAC1 5879 CG2248 B

Memantine MAPT, CYP3A4 4137, 1576 CG31057,CG9438 B

Menatetrenone CYP3A4 1576 CG9438 0

MENT SERPINB3, SERPINB4 6317, 6318 CG9456, CG9456 B

Mephenytoin SERPINB4 6318 CG9456 B

Meprobamate CYP3A4 1576 CG9438 0

MeSAdo JU , MTAP, JUNB , JUN 3725, 4507, 3726, 37 CG2275, CG4802, CG2 B

D 27 275,CG2275

mesalamine JUND 3727 CG2275 B

Mesaton CPA1, JUN, CCNA2 1357, 3725, 890 CG14820,CG2275,CG B

3510

mesoglycan CCNA2 890 CG3510 B

Mesol FGF1 2246 CG4608 B metazachlor FOXD3 27022 CG3668 B

Meth JUNB, MAPT , JUND, 0P 3726, 4137, 3727, 49 CG2275, CG31057, CG 0

RM1, DTN1, JUN 88, 84062, 3725 2275,CG7285,CG685

6,CG2275

methanopterin JUN 3725 CG2275 B

Methorphan CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 0

Methoxsalen CYP4F3 4051 CG3466 B methoxymor- CYP3A4 1576 CG9438 0 phinan

Methylpredni- MBL2, SERPINC1 4153, 462 CG7763, CG9456 B solone

Methylthio- SERPINC1 462 CG9456 B inosine

Metkephamid PPA1 5464 CG4634 0

Metopiron CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 0

Metribolone CDK4, GSK3B, GF7 1019, 2932, 2252 CG5072,CG2621,CG4 B

608

Miazine FGF7 2252 CG4608 B miconazole CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 0

Mictonorm CYP4F3 4051 CG3466 B

Midazolam CYP3A4, CYP4F3, ABC 1576, 4051, 5243, 79 CG9438,CG3466,CG3 0

Bl , MMEL1 258 879,CG9565

Mifepristone CYP3A4 , COR1 , CCNA 1576, 9611, 890, 101 CG9438,CG7951,CG3 B

2 , CDK2 , ABCB1 7,5243 510,CG5363,CG3879 miglustat ABCB1 5243 CG3879 0 milbemycin KDR 3791 CG8222 0

Mimosine ABCB1 5243 CG3879 0 mirtazapine EIF5 1983 CG9177 B

Mit-C JUNB, PPP1R15A, FCN 3726, 23645, 2220, 4 CG2275, CG3825, CG5 0

2 , MAF, JUN, SHH, JUN 094, 3725, 6469, 372 55, CG10034, CG2275

D 7 ,CG4637,CG2275 mithramycin A JUND 3727 CG2275 B

Mitoxantrone ABCB1 , KLHL1 , JUN 5243, 57626, 3725 CG3879, CG17754, CG 0

2275

MK-0524 JUN 3725 CG2275 B

MLN 944 TFDP1 7027 CG4654 B

Molsidomine JUN 3725 CG2275 B

Monensin HRB,HSPA4,CDK2,CC 3267, 3308, 1017, 89 CG3365,CG6603,CG5 0

NA2,CDC2, PLAT,CCN 0, 983, 5327, 595, 10 363, CG3510, CG5363

Dl, CDK6, CDK4 21, 1019 ,CG13744,CG9096,C

G5072, CG5072 monocillin I CYP3A4 1576 CG9438 0 monodansylca- HSP90AA1 3320 CG1242 0 daverine

mono-N- CDK4 1019 CG5072 0 demethy- ladinazolam

Monorden HSP90AB1, HSPA4, FG 3326, 3308, 2247, 33 CGI 242, CG6603, CG4 B F2, DNAJBl, HSP90AA 37, 3320 608,CG10578,CG124

1 2

MORIN JUND, JUNB, ABCBl, J 3727, 3726, 5243, 37 CG2275, CG2275,CG3 0

UN 25 879,CG2275

morphine- 3- JUN 3725 CG2275 B glucuronide

mosapride HTR4, (CYP3A4) 3360, (1576) CG6919, (CG9438) 0 motapizone HTR4 3360 CG6919 0

Motuporin MME 4311 CG9565 0 moxifloxacin PPP2CA 5515 CG7109 0

MRK 003 NOTCH4, NOTCH3 4855, 4854 CG3936, CG3936 B

MTPA NOTCH3 4854 CG3936 B

Muran PLG 5340 CG13744 0

Muscarine FOXD3 27022 CG3668 B

N- (4- CCND1 595 CG9096 B amino- phenethyl) spi

roperidol

N- (4- ABCBl 5243 CG3879 0 amino- phenyl) maleim

ide

N- ( 4-cyano- CYP3A7, CYP3A4 1551, 1576 CG9438, CG9438 0 benzo (b) thiop

hene-2- car- bonyl) guanidi

ne

N- (8-amino-l- CYP3A4 1576 CG9438 0 carboxyoc- tyl ) -alanyl- proline

(alpha) - (4- HTR1A 3350 CG7485 0 amino-4- deoxyp- teroyl ) -

N (delta) - hemiphthaloyl

-L-ornithine

N- (m-heptyl) - FGF1 2246 CG4608 B 5-chloro-l- naphthalene- sulfonamide

N-3- HSP90AA1 3320 CG1242 0 isoquino- linyl-2- ( (4- pyridinyl- methyl) amino)

benzamide

NABU SLC19A1 6573 CG14694 0

Naftalen GORASP1 64689 CG7809 B

Naloxone CYP3A4 1576 CG9438 0

Naltrexone OPRM1 4988 CG7285 B naltrindole OPRM1 4988 CG7285 B

NAN-190 hy- OPRK1 4986 CG7285 B drobromide

nanchangmycin HTR1A 3350 CG7485 0

Naphazoline NDU AB1 4706 CG9160 0

NARIGENIN CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 0 nateglinide ABCB1 5243 CG3879 0

N- KDR 3791 CG8222 0 benzyloxycar- bonylprolyl- prolinal

N- PREP 5550 CG5355 0 dehy- droxyzileuton

N- CYP4F3 4051 CG3466

desmethylclo- bazam

nedaplatin CYP3A4 1576 CG9438 0

Nefazodone CYP4F3,CYP3A4,HTR 4051, 1576, 3350 CG3466,CG9438,CG7

1A 485

Nelfinavir CYP4F3, CSE1L, CYP3 4051, 1434, 1576, 52 CG3466, CG13281, CG

A4 , ABCB1 43 9438, CG3879 nemonapride ABCB1 5243 CG3879 0 neodymium HTR1A 3350 CG7485 0

Neomycin MAPT 4137 CG31057 B

N- GTF3C1, HSPA4, EYA1 2975, 3308, 2138 CG7099,CG6603,CG9 ethylmaleim- 554 ide

netoglitazone SERPINB1 1992 CG9456 B neuromedin C TSC1 7248 CG6147 0 Neut CCND1,0DC1 595, 4953 CG9096, CG8721 B

Nevirapine CSE1L, ABCBl, KLHL1 1434, 5243, 57626, 1 CGI 3281 , CG3879 , CG 0

, CYP3A4 576 17754, CG9438

Niacinamide TUBA1B, GF6 , MAPT , 10376, 2251, 4137, 1 CG1913,CG4608,CG3 B

CYP3A4 576 1057, CG9438 nicaraven CYP3A4 1576 CG9438 0

Nicardipine CYP3A4, ABCBl 1576, 5243 CG9438, CG3879 0

Niceritrol ABCBl 5243 CG3879 0

Nigericin LPA 4018 CG13744 0 niguldipine EIF4G1 1981 CG10811 B

Nimodipine ABCBl 5243 CG3879 0

NK 104 RAC1, FGF2, PLAT 5879, 2247, 5327 CG2248,CG4608,CG1 B

3744

NMDA FOXD3,MAP2, DMRT1, 27022, 4133, 1761, 3 CG3668, CG31057, CG 0

HTR1A, METAP2 350, 10988 11094, CG7485, CG40

08

N- PLAT, CYP4F3 5327, 4051 CG13744,CG3466 0 methylsul- fonyl-6- (2- propargyloxy- phenyl) hexana

mide

NN 703 METAP2 10988 CG4008 B

Nobiletin ABCBl , JUN, JUND, CY 5243,3725,3727,15 CG3879, CG2275, CG2 O

P3A4, JUNB 76,3726 275,CG9438,CG2275

NOC 18 JUNB 3726 CG2275 B Nociceptin OPRL1 , SSTR4 , HTR1A 4987,6754,3350,67 CG7285, CG7285, CG7 B

, SSTR1, OPRM1 51,4988 485, CG7285, CG7285 noralfentanil OPRM1 4988 CG7285 B

Norbinaltor- CYP3A4 1576 CG9438 0 phimine

norcantha- OPRK1 4986 CG7285

ridin

Nordihy- JUN, IGFIR, JUND, JU 3725, 3480, 3727, 37 CG2275, CG1842 , CG2 B droguaiaretic NB 26 275,CG2275

Acid

Norethindrone PLAT, CYP3A4 5327, 1576 CG13744, CG9438 0 noreximide CYP3A4 1576 CG9438 O norfluoxetine CYP4F3, CYP3A4 4051, 1576 CG3466, CG9438 B norlauda- JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2 B nosoline 275

Nortilidine ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 O norverapamil CYP3A4 1576 CG9438 O novobiocin HSP90AA1, PCSK5, CD 3320, 5125, 11140 CG1242, CG10772, CG O

C37 12019

NPI 031L TSC1,RAC1, IGF1R, M 7248, 5879, 3480, 44 CG6147,CG2248,CG1 B

SN, MAPT , KCNK6 , PDC 78, 4137, 9424, 5134 842,CG10701,CG310

D2, PCSK7, JUND, FAA , 9159, 3727, 2166, 9 57,CG1688,CG326,C

H,NCOR1,HSP90AA1, 611, 3320, 6317, 595 G10772, CG2275, CG6

SER- , 64689, 3726, 2247, 007,CG7951,CG1242

PINB3 , CCND1 , GORAS 2252, 3082, 5243, 89 ,CG9456,CG9096,CG

PI, JUNB, FGF2, FGF7 1, 3309, 983, 3718, 3 7809,CG2275,CG460

, HGF, ABCB1 , CCNB1 , 725, 1591, 7439 8,CG4608,CG13744,

HSPA5, CDC2, JAK3 , J CG3879,CG3510,CG5

UN, CYP24A1, BEST1 436,CG5363,CG1594

,CG2275,CG6042,CG

6264

NRDC BEST1 7439 CG6264 B

NSC 23766 RACl,NOTCHl 5879, 4851 CG2248, CG3936 B

NSC 295558 NOTCH1 4851 CG3936 B

NSC 366140 CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O

NSC 663284 CYP4F3 4051 CG3466 B

N-tert-butyl- CYP4F3 4051 CG3466 B

3- [4- (2- methoxy- phenyl) pipera

zin-l-yl] -2- phenylpro- panamide

NU2058 CDC2 983 CG5363 B

NU6102 CDK2 1017 CG5363 B nutlin 3 CDK4 1019 CG5072 O

NVP-AEW541 ABCB1 5243 CG3879 O obovatol JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2 B

275

OC 144-093 JUN 3725 CG2275 B ochratoxin A KLHL1, FOXD3 57626, 27022 CG17754,CG3668 O Octreotide SSTR5 , FGF2 , SSTR1 , 6755, 2247, 6751, 34 CG7285,CG4608,CG7 B

IGF1R, GF3 , PPA1 80, 2248, 5464 285,CG1842,CG4608

,CG4634

Octreotide PPA1 5464 CG4634 O

0- IGF1R 3480 CG1842 O demethyl- tramadol

0- OPRM1 4988 CG7285 B desethylre- boxetine

oenothein B SSTR2 6752 CG7285 B

Ogen FGF2, PLG 2247, 5340 CG4608, CG13744 B

OH-pro PLG 5340 CG13744 O

Oktan MBL2 4153 CG7763 B

Olamine OPRM1 4988 CG7285 B olanzapine MEA1 4201 CG14341 O oleandrin JUN, JUND, JUNB 3725, 3727, 3726 CG2275, CG2275, CG2 B

275

oleylamide JUNB 3726 CG2275 B olmelin JUNB, JUN, JUND 3726, 3725, 3727 CG2275, CG2275, CG2 B

275

olomoucine MAPT, CDC2, CDK2, CD 4137, 983, 1017,101 CG31057, CG5363, CG B

K4 9 5363, CG5072

Olymp CDK4 1019 CG5072 O omalizumab PDXP 57026 CG4755 B omapatrilat CYP3A4 1576 CG9438 O omega-N- MME 4311 CG9565 O

Methylargin- ine

Omeprazole ABCB1 , CYP3A , CYP4 5243, 1576, 4051 CG3879,CG9438,CG3 O

F3 466

omeprazole CYP4F3 4051 CG3466 B sulfone

Ondansetron CPA1, CYP3A4, ABCB1 1357, 1576, 5243 CG14820,CG9438,CG O

3879

ONO 1301 ABCB1 5243 CG3879 O

Optef PI 1 , PCBD1 , VEGFC , P 8909, 5092, 7424, 98 CG2145,CG1963,CG7 O

SMD6, HSPB8, TNC, CC 61, 26353, 3371, 595 103,CG5378,CG1420

ND1 , ABCB1 , CPA1 , PI , 5243, 1357, 5286, 3 7,CG5550,CG9096,C

K3C2A, HGF, SERPINC 082, 462, 1576, 3350 G3879,CG14820,CG1 1,CYP3A4,HTR1A,NU , 8021 1621, CG13744, CG94

P214 56,CG9438,CG7485,

CG3820

Org 31540 NUP214 8021 CG3820 B

Orphenadrine HGF 3082 CG13744 O

OSI 930 CYP3A4 1576 CG9438 O

OSU 03012 CCNA2,HSPA4 890,3308 CG3510, CG6603 B

Ouabain MAPT, ABCB1, JUN, AT 4137, 5243, 3725, 49 CG31057,CG3879,CG B

P4B, FGF13, GF2 6, 2258, 2247 2275,CG9258,CG460

8,CG4608

ovalicin FGF2 2247 CG4608 B

Ovex CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O oxaliplatin NOTCH1 , TXNL1 , CDC2 4851, 9352, 983 CG3936,CG5495,CG5 O

363

oxatomide CDC2 983 CG5363 B oxcarbazepine CYP3A4 1576 CG9438 O

Oxidopamine CCND1, JUN,GSK3B 595, 3725, 2932 CG9096,CG2275,CG2 B

621

oxymatrine GSK3B 2932 CG2621 B

Oxytrol CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 O

Paclitaxel MAPT, JUND, CCND1, J 4137, 3727, 595, 372 CG31057,CG2275,CG B

UN, TMSB4X, TUBA1B, 5, 7114, 10376, 3315 9096,CG2275,CG494

HSPB1, PSMD2,EIF4E , 5708, 1979, 1678, 1 4,CG1913,CG14207,

2,TIMM8A,EIF4E1,C 978, 891, 983, 8766, CG7762,CG8846,CG1

CNB1, CDC2,RAB11A, 5243, 2932, 2717, 64 728,CG8846,CG3510

ABCB1 , GSK3B, GLA, G 689, 3316, 1434, 372 ,CG5363,CG5771,CG

ORASP1, HSPB2, CSE1 6, 1576 3879,CG2621,CG573

L, JUNB, CYP3A4 1,CG7809,CG14207,

CG13281,CG2275,CG

9438

palytoxin CYP3A4 1576 CG9438 O pamidronate JUN 3725 CG2275 B p- CYP4F3 4051 CG3466 B

Aminohippuric

Acid

panaxadiol BEST1 7439 CG6264 B pantoprazole CDK2 1017 CG5363 B

PAPP CYP3A4 1576 CG9438 O

Parthenolide GORASP1 , ADAMTS4 , H 64689, 9507, 3303 CG7809, CG14869, CG O

SPA1A 5436 Patulin HSPA1A 3303 CG5436 0 pazopanib KDR, (EGR1) 3791, (1958) CG8222, (CG7847)

PCSO KDR 3791 CG8222 0

PD 169316 HSPB1, ATF2, HSPB2 3315, 1386, 3316 CG14207,CG30420,C B

G14207

PD 173074 HSPB2 3316 CG14207 B PD 98059 PAX6, JUN, GORASP1, 5080, 3725, 64689, 3 CGI 1186, CG2275, CG B

JUND, NPDC1, PHOX2A 727, 56654, 401, 372 7809, CG2275, CG304 , JUNB,PPA1,FGF2,C 6, 5464, 2247, 1591, 20, CG11182, CG2275 YP24A1 , ADAMTS 9 , EG 56999, 1958, 3082, 5 ,CG4634,CG4608,CG Rl , HGF, PLG, ABCB1 , 340, 5243, 595, 2258 6042, CG14869, CG78 CCND1,FGF13,CDK2, , 1017, 2220 47, CG13744, CG1374 FCN2 4,CG3879,CG9096,C

G4608,CG5363, CG55 5

PDBU ETV4, ABCB1 2118, 5243 CG6892, CG3879 O

Pectenotoxin CDC2, EGR1 983, 1958 CG5363, CG7847 B II

pegvisomant EGR1 1958 CG7847 0 Pemetrexed SLC19A1,TBXAS1,MT 6573, 6916, 4507 CGI 4694, CG3466, CG B

AP 4802 pentosidine MTAP 4507 CG4802 B PentoxifylTSC1, CCNB1, FCN2 7248, 891, 2220 CG6147, CG3510, CG5 B line 55

Peplomycin GORASP1, PREP 64689, 5550 CG7809, CG5355 B Pepstatin A CYP3A4, PLG 1576, 5340 CG9438, CG13744 O Perazine PLG 5340 CG13744 O Perillol JUN, JUNB, JUND 3725, 3726, 3727 CG2275,CG2275,CG2 B

275

Perindopril JUND 3727 CG2275 B perylene MBL2 4153 CG7763 B bisimide

phen MAPT 4137 CG31057 B phen PHC2 1912 CG18414 O phenanthrene MMEL1 79258 CG9565 O phenothiazi- CYP4F3 4051 CG3466 B nes

Phenprocoumon CSE1L,CYP3A4 1434, 1576 CG13281, CG9438 O Phenytoin CYP3A4 , CYP4F3 , KLH 1576, 4051, 57626 CG9438,CG3466,CG1 B

LI 7754 pheophorbide KLHL1 57626 CG17754 0 phloretin GSK3B, TXNIP 2932, 10628 CG2621, CG18745 B

Picibanil TXNIP 10628 CG18745 B picric acid SMARCA2 6595 CG5942 B picropodo- PDXP 57026 CG4755 B phyllin

pidotimod IGF1R 3480 CG1842 0 pifithrin CCNB1,HSP90AA1 891, 3320 CG3510, CG1242 B pindobind HSP90AA1 3320 CG1242 0 pioglitazone SER- 462, 64689, 1576, 37 CG9456,CG7809,CG9 B

PINC1,G0RASP1,CYP 26, 3725, 3727 438, CG2275, CG2275

3A4 , JUNB, JUN, JUND , CG2275

Piroxicam JUNB, SERPINB3, JUN 3726, 6317, 3725, 37 CG2275,CG9456,CG2 B

, JUND 27 275,CG2275

plumbagin G0RASP1,CDC2 64689, 983 CG7809, CG5363 B

Pluronic p 85 ABCB1 , KLHL1 5243, 57626 CG3879, CG17754 0

PMPA KLHL1 57626 CG17754 0

PMS KLHL1 57626 CG17754 0 posaconazole FAAH 2166 CG6007 B

PP-IX CYP3A4 1576 CG9438 0

Pragmoline ABCB1 5243 CG3879 0

Pravastatin CYP3A4, RAC1, JUNB, 1576, 5879, 3726, 37 CG9438,CG2248,CG2 B

JUND, ABCB1, CYP4F3 27, 5243, 4051, 3725 275,CG2275,CG3879

, JUN, PLAT , 5327 , CG3466,CG2275, CG

13744

Prazosin PLAT 5327 CG13744 0

PRDL FOXD3 , CYP3A4 , SMAR 27022, 1576, 6598, 3 CG3668,CG9438,CG1 B

CB1, JUN, PLG 725,5340 064,CG2275,CG1374

Prednisone MME , NF2 , SERPINC1 , 4311, 4771, 462, 524 CG9565, CG14228, CG 0

ABCB1 , BEST1 3, 7439 9456, CG3879,CG626 preussin BEST1 7439 CG6264 B

Primidone CDK2 1017 CG5363 B

Proadifen CYP3A4 1576 CG9438 0

Procasil SLC5A5, HSPA1A 6528, 3303 CG32669,CG5436 0

Procetofen CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 0

Prodigiosin ABCB1 5243 CG3879 0

Prodix GSK3B 2932 CG2621 B Promegestone CYP3A4 1576 CG9438

Propofol FAAH, CYP3A4 2166, 1576 CG6007, CG9438 prostaglandin CYP3A4 1576 CG9438

Al

prostaglandin SSTRl, TFDPl, GSK3B 6751,7027,2932, 67 CG7285, CG4654 , CG2 B D2 , SSTR4, HTR1A 54, 3350 621,CG7285,CG7485 prostaglandin HTR1A 3350 CG7485 0 El

prostaglandin FGF2, FLT4, SERPINB 2247,2324,5269 CG4608 , CG8222 , CG9 0 F2alpha 6 456

prostaglandin CYP4F12,CYP4F8 66002,11283 CG9438 , CG3466 0 H2

prostaglandin HSPA4 , KHDRBS1 3308, 10657 CG6603, CG4816 0 J2

prostaglandHGF, ATPIB1 , CYP24A 3082, 481, 1591 CG13744,CG9258,CG 0 ins 1 6042

prostaglandGORASP1 , KDR 64689, 3791 CG7809, CG8222 B ins G

prostratin CCNT1,CCNT2 904, 905 CG6292, CG6292 prucalopride HTR4, (CCNT2) 3360, (905) CG6919, (CG6292) prunustatin A HTR4 3360 CG6919

Pseudo- HSPA5 3309 CG5436

hypericin

pseudolaric CYP3A4 1576 CG9438 0 acid B

psilocybin JAG1 182 CG6127 0 Psoralens ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 0 PTAP CYP3A4 1576 CG9438 0 PTX-B JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2 B

275

puerarin JUN 3725 CG2275 B Pugnac JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2 B

275

p-XSC KLHL1 57626 CG17754 0 Pyrethrins CYP3A4, CYP4F3 1576, 4051 CG9438, CG3466 0 pyrvinium HSP90B1,HSPA5 7184, 3309 CG1242, CG5436 0 quercitrin HSPA5 3309 CG5436 0 quetiapine HTR1A, CYP3A4 3350, 1576 CG7485, CG9438 0 Quicifal CYP3A4 1576 CG9438 0 quinupristin- CYP3A4 1576 CG9438 0 dalfopristin

R 101933 CYP3A4 1576 CG9438 0 rabeprazole ABCBl 5243 CG3879 0 radester ABCBl 5243 CG3879 0

Raloxifene JUND,NC0R1, JUNB, A 3727, 9611, 3726, 52 CG2275, CG7951,CG2 B

BCB1 , BEST1 , JUN, CY 43, 7439, 3725, 1576 275,CG3879,CG6264

P3A4 ,CG2275,CG9438 ramiprilat JUN, JUND, BNl , JUN 3725, 3727, 2200, 37 CG2275,CG2275,CG3 B

B 26 936,CG2275

rebamipide JUNB 3726 CG2275 B reboxetine JAG1 182 CG6127 0 remifentanil CYP3A4 1576 CG9438 0 renzapride HTR4, (OPRM1) 3360, (4988) CG6919, (CG7285) B repaglinide HTR4 3360 CG6919 0

Requip CYP3A4 1576 CG9438 0

Revex JUN 3725 CG2275 B

Rhodinal OPRK1 4986 CG7285 B

Riacon HSPB1,HSPB2 3315, 3316 CG14207,CG14207 B

Ribavirin HSPB2 3316 CG14207 B

Rifabutin CYP3A4,HSP90AA1,C 1576, 3320, 4051 CG9438,CG1242,CG3 0

YP4F3 466

Riluzole CYP4F3 4051 CG3466 B rimorphin HSPA4 3308 CG6603 0 risedronic OPRK1 4986 CG7285 B acid

risperidone CYP3A4, ABCBl 1576, 5243 CG9438, CG3879 0

Ritodrine ATP2B2, ATP2B2 491, 491 CG2167, CG2172 0

Ritonavir CYP3A7 , NF2 , CYP27A 1551, 4771, 1593, 52 CG9438, CG14228, CG B

1,ABCB1,CYP24A1,C 43, 1591, 1576 6042,CG3879,CG604

YP3A4 2,CG9438

rituximab JUND, JUNB, JUN, PDP 3727, 3726, 3725, 51 CG2275,CG2275,CG2 B

Kl, ABCBl 70, 5243 275, CG1210, CG3879

RMI 12330A ABCBl 5243 CG3879 0

Ro 13-8996 CYP27A1 1593 CG6042 B

Ro 64-0802 CYP3A4 1576 CG9438 0

Robitet ABCBl , SLC5A6, CCND 5243, 8884, 595, 532 CG3879, CG32669, CG 0

1 , PLAT, FGF2 , HGF, T 7, 2247, 3082, 1678, 9096, CG13744, CG46

IMM8A, HSPA4 3308 08, CG13744, CG1728

, CG6603

Rolipram CHAT, MAPT 1103, 4137 CG12345, CG31057 0 romidepsin JUND, JUNB, ABCB1, J 3727, 3726, 5243, 37 CG2275,CG2275,CG3 O

UN 25 879,CG2275

ropivacaine JUN 1678 CG1728 O Roquefortine CYP3A4 3308 CG6603 O roscovitine HSPB1 , HSPB2 , GORAS 3315, 3316, 64689, 4 CG14207,CG14207,C B

P1,MAPT,CDK6,CCND 137, 1021, 894, 904, G7809,CG31057,CG5 2,CCNT1,CCND1,CDC 595, 983, 1017 072,CG9096,CG6292 2,CDK2 ,CG9096,CG5363,CG

5363

rosiglitazone ATP2A2 , JUND, JUNB, 488, 3727, 3726, 724 CG32451,CG2275,CG B

TSC1, JUN, GORASP1, 8, 3725, 64689, 3480 2275,CG6147,CG227 IGF1R, CYP3A4, CIDE , 1576, 1149 5,CG7809,CG1842,C A G9438,CG1975 rosmarinic JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2 O acid 275

rosuvastatin ABCB1 , KLHL1 , SLC22 5243, 57626, 10864 CG3879, CG17754, CG O

A7 8654

Rozevin JUN, KLHL1 , MAPT, CD 3725, 57626, 4137, 9 CG2275, CG17754, CG O

C2, ABCB1, JUNB, JUN 83, 5243, 3726, 3727 31057, CG5363,CG38 D 79, CG2275, CG2275

RPR 121056 JUND 10864 CG8654 O

Rulid SLC5A5, ABCB1, LT1 6528, 5243, 2321 CG32669,CG3879,CG B

8222

rutecarpine FLT1 983 CG5363 B Rutin ABCB1,HSPA4,HSP90 5243, 3308, 3320 CG3879,CG6603,CG1 B

AA1 242

S 17092-1 PREP, (HSP90AA1) 5550, (1576) CG5355, (CG9438) O

S 9788 PREP 6528 CG32669 O

S azabisabo- ABCB1 5243 CG3879 O lene

Safingol PPA1 2321 CG8222 O SAHA KPNA2, ADAMTS1, JAK 3838, 9510, 3716, 59 CG4799, CG14869, CG O

1,CCND1, JUND, JUN, 5, 3727, 3725, 10628 1594,CG9096,CG227 TXNIP, DAB1, HSP90A , 1600, 3320, 3726 5,CG2275,CG18745, Al , JUNB CG9695,CG1242,CG2

275

saintopin JUNB 3716 CG1594 B

Salicin SSTR1 , SSTR4 , HTR1A 6751,6754,3350 CG7285,CG7285,CG7 B

485

salinomycin HTR1A 10628 CG18745 B salinospora- ABCB1 1600 CG9695 O mide A

salubrinal EIF2S1, HSPA5 1965, 3309 CG9946, CG5436 B salvin HSPA5 7153 CG10223 B salvinorin A CCNA2 6751 CG7285 B samarium OPRK1 6754 CG7285 B sampatrilat PSMD6 3350 CG7485 O sangivamycin MME 5243 CG3879 O

Saquinavir CYP3A7 , ABCB1 , CYP3 1551, 5243, 1576 CG9438,CG3879,CG9 O

A4 438

Sarasar CYP3A4, KLHL1 1576, 57626 CG9438, CG17754 B sarizotan KLHL1 9861 CG5378 O

SB 203580 CCNB1,EGR1, PLAT, P 891, 1958, 5327, 114 CG3510,CG7847,CG1 B

GLYRP2, PLG, HSPB2, 770, 5340, 3316, 372 3744, CG14704, CG13

JUND, SSTR4 , JUN, JU 7, 6754, 3725, 3726, 744,CG14207,CG227

NB, SSTR1, GORASP1, 6751, 64689, 983, 33 5,CG7285,CG2275,C

CDC2, HSPBl, HGF, CY 15, 3082, 1594, 3350 G2275,CG7285,CG78

P27B1,HTR1A,ATF2, , 1386, 595, 890 09,CG5363,CG14207

CCND1,CCNA2 ,CG13744,CG6042,C

G7485,CG30420,CG9

096,CG3510

SB 207266 HTR4, (CCNA2) 3360, (983) CG6919, (CG5363) O

SB 216763 CCND1 , GSK3B, GSK3A 595, 2932, 2931, 488 CG9096,CG2621,CG2 O

, ATP2A2 621,CG32451

SB 225002 HTR1A, SSTR1, SSTR4 3350, 6751, 6754 CG7485,CG7285,CG7 B

285

SB 415286 GSK3B, RAC1 , GSK3A 2932, 5879, 2931 CG2621,CG2248,CG2 B

621

SB-649915 GSK3A 2931 CG2621 B

SB-706375 HTR1A 488 CG32451 B

SCH 66712 RPS6KA2 3350 CG7485 O schizandrin B CYP3A4 6751 CG7285 B

SCIO-469 HSPBl, HSPB2 3315, 3316 CG14207,CG14207 B scoparone HSPB2 5879 CG2248 B

Sediel GORASP1 2931 CG2621 B selamectin HTR1A 3350 CG7485 O

Selegiline ABCB1 6196 CG17596 O

Serad JUN 1576 CG9438 O sesamin CYP3A4 5243 CG3879 O sevoflurane JUN, PIK3C2A, JUNB, 3725, 5286, 3726, 37 CG2275, CG11621, CG O JUND 27 2275, CG2275

Sildenafil JUND 5243 CG3879 O silybin CCND3, JUND, JUNB, I 896, 3727, 3726, 348 CG9096,CG2275,CG2 B

GF1R, JUN, GORASP1 , 0, 3725, 64689, 1576 275, CG1842, CG2275

CYP3A4 , CDK2 , ABCB1 , 1017, 5243, 595 ,CG7809,CG9438,CG

, CCND1 5363,CG3879,CG909

Ό

Sizofiran CCND1 3726 CG2275 B sofalcone WNK1 3480 CG1842 O sorafenib KDR, GSK3B, PSMB5, C 3791, 2932, 5693, 59 CG8222,CG2621,CG1 B

CND1, CYP3A4,EIF2S 5, 1576, 1965 2323,CG9096,CG943

1 8,CG9946

SP 100030 JUN, JUNB, JUND 3725, 3726, 3727 CG2275, CG2275, CG2 O

275

sparfloxacin JUND 2932 CG2621 B spiradoline ABCB1 5693 CG12323 O spiraprilat OPRK1 595 CG9096 B spiroger- CSE1L 1576 CG9438 O manium

SR 48692 SERPINB1, EGR1 1992, 1958 CG9456, CG7847 B

SR 59230A EGR1 3726 CG2275 B

SRI 63-154 RAC1 3727 CG2275 B

SRIH SSTR3, SSTR4, SSTR1 6753, 6754, 6751, 67 CG7285,CG7285,CG7 O

, SSTR5 , MAGT1 , SSTR 55, 84061, 6752 285,CG7285,CG7830

2 , CG7285

ST 1481 SSTR2 5879 CG2248 B

STA 5326 ABCB1 9159 CG10772 O stachybotry- RPSA 6753 CG7285 B dial

Stanozolol PLG 6754 CG7285 B

Stavudine SERPINC1 6751 CG7285 B

SU 1498 CSE1L 6755 CG7285 B

SU 5416 KDR (84061), 3791 (CG7830), CG8222 O

SU 5614 KDR 6752 CG7285 B

SU 6656 KDR 5243 CG3879 O

SU 6668 RAC1 3921 CG14792 O

SU 9516 CDK2, CCND1 1017, 595 CG5363, CG9096 B

Sucralfate CCND1 1434 CG13281 O

Sufentanil PHC2 3791 CG8222 O

Sulem OPRM1 3791 CG8222 O Sulfamerazine HSPA4 3791 CG8222 O

SulMYB 5879 CG2248 B famethazine

sulfamide CYP3A4 3791 CG8222 O

Sulfaphena- JUNB, JUND, CYP4F3, 3726, 3727, 4051, 37 CG2275,CG2275,CG3 B zole JUN, CYP3A5 25, 1577 466,CG2275,CG3466

Sulfoximine JUN 3308 CG6603 O

Sulindac CCND1 , TSC1 , ABCB1 595, 7248, 5243 CG9096, CG6147, CG3 B

879

sultopride ABCB1 3726 CG2275 B

Sumatriptan ABCB1 3727 CG2275 B sunitinib KDR, CYP3A4 3791, 1576 CG8222, CG9438 B sural MMEL1 , RPSA 79258, 3921 CG9565, CG14792 B

T 0901317 RPSA 7248 CG6147 O

TAC 101 JUNB, JUND, JUN 3726, 3727, 3725 CG2275, CG2275, CG2 O

275

Tacrolimus CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O

Tamogel CCND2,CYP3A4 894, 1576 CG9096, CG9438 O tamsulosin CYP3A4 1576 CG9438 O tandospirone CYP3A4, HTR1A 1576, 3350 CG9438, CG7485 B

Tangeretin HTR1A 3725 CG2275 B tanshinone ABCB1,CYP3A4 5243, 1576 CG3879, CG9438 O tariquidar CYP3A4 894 CG9096 B

Taseron ABCB1 1576 CG9438 O

Taurolin HTR1A 146 CG18741 O

TAXOTERE KLHL1 , GLA, NK1 , CC 57626, 2717, 65125, CG17754,CG5731,CG O

ND1,CYP4F3,RAC1,A 595, 4051, 5879, 524 7177,CG9096,CG346

BCB1, CCNB1, TUBA1B 3, 891, 10376, 983, 1 6,CG2248,CG3879,C

,CDC2,CYP3A4 576 G3510,CG1913, CG53

63, CG9438

tazarotene TSC1, APC 7248, 324 CG6147, CG6193 B

TBDZ CYP4F3, HSPA5, HSPA 4051, 3309, 3308 CG3466,CG5436,CG6 B

4 603

TBHQ JUND, JUNB, JUN 3727, 3726, 3725 CG2275,CG2275,CG2 O

275

TCDD JUN, PLAT, CYP3A7, P 3725, 5327, 1551, 10 CG2275, CG13744, CG B

PIF, ABCB1, CYP27B1 105, 5243, 1594, 05 9438,CG2852,CG387

, CYP4F3 1 9,CG6042,CG3466

Tegafur WNK1 , MAGT1 65125, 84061 CG7177, CG7830 B tegaserod HTR4, (MAGT1) 3360, (5327) CG6919, (CG13744) O telithromycin HTR4 1551 CG9438 0 telmisartan CYP3A4 10105 CG2852 0 temozolomide EIF2S1,CDC2 1965, 983 CG9946, CG5363 B temsirolimus CCND1,CYP3A4 595, 1576 CG9096, CG9438 0 Teniposide TOP2B, JUN 7155, 3725 CG10223, CG2275 0 Terfenadine JUN 1576 CG9438 0

Teriparatide PLG, BEST1 , HSPA4 5340, 7439, 3308 CG13744,CG6264, CG B

6603

Tetraprenol HSPA4 595 CG9096 B TG101209 TBXAS1 1576 CG9438 0 thalicarpine JAK2 7155 CG10223 B Thapsigargin CDK2, HSPB1, HSPA4, 1017, 3315, 3308, 33 CG5363, CG14207, CG 0

HSPB2,RPSA, HSP90B 16, 3921, 7184, 3350 6603, CG14207, CG14 1 , HTR1A, HSPA1A, JU , 3303, 3725, 3304, 5 792,CG1242,CG7485 N, HSPAIB, ABCBl, HS 243, 3309, 3306, 293 , CG5436, CG2275, CG PA5,HSPA2,GS 3B,X 2, 7494 31449, CG3879,CG54

36,CG5436,CG2621, CG9415

Theaflavin JUND, JUNB, JUN 3727, 3726, 3725 CG2275,CG2275,CG2 B

275

Thiazolidin- NRF1, CYP3A4, BEST1 4899,1576,7439,59 CG3114, CG9438, CG6 B ediones ,CCND1 5 264,CG9096

thiocoraline CCND1 7494 CG9415 B thioridazine CYP3A4 3727 CG2275 B

Thiorphan MME , ECE1 4311,1889 CG9565, CG9565 B thromboxane ECE1 4899 CG3114 B

B2

thulium SERPINC1 1576 CG9438 0 thymalfasin ABCBl, JUND, JUN, JU 5243, 3727, 3725, 37 CG3879, CG2275, CG2 0

NB 26 275,CG2275

Thymopentin JUNB 4311 CG9565 0 thymoquinone MME 1889 CG9565 0 Ticlopidine SERPINC1, CYP4F3 462,4051 CG9456, CG3466 B Tilidine CYP3A4, CSE1L, ABCB 1576,1434,5243 CG9438, CG13281, CG B

1 3879 tipifarnib GORASP1, ABCBl 64689, 5243 CG7809, CG3879 0 tipranavir ABCBl 64689 CG7809 B tirilazad CYP3A4 462 CG9456 B

TKI-31 CYP3A4 4051 CG3466 B

Tmndga KDR 1576 CG9438 0 MPN ABCB1 1434 CG13281 0 Toddalin JUN,HSPB1,G0RASP1 3725, 3315, 64689 CG2275, CG14207, CG 0

7809

Todralazine G0RASP1 1576 CG9438 0 tofisopam PREP 1576 CG9438 0 Tolterodine CYP4F3, CSE1L 4051, 1434 CG3466, CG13281 0 topiramate CSE1L 3725 CG2275 B Topotecan HSPA4 , CYP3A , ABCB 3308, 1576, 5243 CG6603, CG9438, CG3 B

1 879

Toremifene ABCB1 5550 CG5355 0 Toxaphene SERPINC1 1576 CG9438 0 Tramadol TSC1 4051 CG3466 B Tramat HSP90B1,MAPT, CCND 7184, 4137, 595, 176 CG1242, CG31057, CG 0

1, DMRT1, HSP90AA1 1,3320 9096, CG11094, CG12

42

trandolapril HSP90AA1 462 CG9456 B Trapidil PLAT 7248 CG6147 0 trapoxin A FGF2 5243 CG3879 0 trastuzumab CCNA2,CCND1,PDPK1 890, 595, 5170, 1279 CG3510,CG9096,CG1 B

, UHMK1, TOP2A, CDK2 33, 7153, 1017, 4851 210,CG3162,CG1022 , OTCH1 , RAC1 , CDK6 , 5879, 1021 3,CG5363,CG3936,C

G2248,CG5072

Trazodone CDK6 595 CG9096 B

Tremode ABCB1 5170 CG1210 B triazolam CYP3A4 127933 CG3162 0 triazoloben- CYP3A4 7153 CG10223 B zodiazepines

tributylstan- PLAT 1017 CG5363 B nane

trichostatin CYP4F3 4851 CG3936 B A

trichostatins CDK6, CCND1, CDK4 1021, 595, 1019 CG5072, CG9096, CG5 0

072

TrifluopABCB1 , EGR1 5243,1958 CG3879, CG7847 0 erazine

trioctyl MYBL2 , TFDP1 , APC , M 4605,7027,324,460 CG9045, CG4654 , CG6 0 phosphine oxYB 2 193,CG9045

ide

Triolein MYB 595 CG9096 B triptolide JUND, JUNB, JUN, GOR 3727,3726,3725,64 CG2275, CG2275, CG2 0 ASPI , HSPA4 , GSK3B 689,3308,2932 275,CG7809,CG6603

,CG2621

TRK 820 GSK3B 4602 CG9045 B troglitazone CYP3A7 , CYP3A4 , JUN 1551, 1576, 3727, 46 CG9438,CG9438,CG2 B

D, MYB, JUN, EGR1 , CD 02, 3725, 1958, 983, 275,CG9045,CG2275

C2, JUNB, CDK4, CDK2 3726, 1019,1017, 10 ,CG7847,CG5363,CG

,CDK6,CCND1,CCNE1 21, 595, 898,896, 89 2275,CG5072,CG536

, CCND3, CCND2 4 3,CG5072,CG9096,C

G3938,CG9096,CG90

96

Troleandomy- CYP4F3,CYP3A4,CYP 4051, 1576, 1551 CG3466,CG9438,CG9 B cin 3A7 438

tropisetron HTR4, (CYP3A7) 3360, (1021) CG6919, (CG5072) 0

Trospium HTR4 595 CG9096 B chloride

Tunicamycin CCNA2 , HSPA4 , HSPA5 890,3308,3309,489 CG3510,CG6603,CG5 0

, RF1 , ABCB1 , EIF2S 9, 5243, 1965, 7184, 436,CG3114,CG3879

1,HSP90B1,CCND1 595 ,CG9946,CG1242,CG

9096

tylophorine JU D, JUNB, JUN 3727, 3726, 3725 CG2275, CG2275, CG2 0

275

Tylox OPRM1, ABCB1 4988, 5243 CG7285, CG3879 0 tyrphostin IGF1R, JUND, RAC1 , R 3480, 3727, 5879, 61 CGI 842, CG2275, CG2 B

AG-490 PS6KA1,EGR1, JUN, J 95, 1958, 3725, 3726 248,CG17596,CG784

UNB , CCND1 , RAC1 , AD , 595, 5879, 9507, 37 7,CG2275,CG2275,C

AMTS4, JAK2 17 G9096,CG2248,CG14

869,CG1594

tyvelose JAK2 6195 CG17596 0

U 0126 FCN2, GORASP1, HGF, 2220, 64689,3082,5 CG555,CG7809,CG13 B

CCND1,RPSA, PLAT, J 95, 3921, 5327, 3727 744,CG9096,CG1479

UND, ADAMTS4 , CCNA2 , 9507, 890, 3726, 10 2,CG13744,CG2275,

, JUNB,CDK4,EGR1,A 19, 1958, 5243, 3725 CG14869,CG3510,CG

BCB1, JUN, EGR2 , 1959 2275,CG5072,CG784

7,CG3879,CG2275,C

G7847

U 69593 EGR2 9507 CG14869 0

Ubizol G0RASP1,HSPA4 64689,3308 CG7809, CG6603 B

UH 301 HSPA4 1019 CG5072 0

Usaf B-12 CCNA2 , SERPINC1 , PL 890,462,5340,3309 CG3510,CG9456,CG1 0

G, HSPA5, JUND, PLAT , 3727, 5327, 6573, 1 3744, CG5436, CG227 , SLC19A1,EIF2S1,H 965,3308,2200,372 5,CG13744,CG14694

SPA4 , BN1 , JUNB, JU 6, 3725 ,CG9946,CG6603,CG

N 3936,CG2275,CG227

O

USAN HSPA8,CCND1,MME,S 3312, 595, 4311, 631 CG31449,CG9096,CG B

ER- 7,1017, 7114, 3308, 9565,CG9456,CG536

PINB3 , CDK2 , TMSB4X 57626, 3082 3,CG4944,CG6603,C

, HSPA4, KLHL1, HGF G17754, CG13744

Valproic Acid GSK3B, JUNB, JUN, TS 2932, 3726, 3725, 72 CG2621, CG2275, CG2 0

CI, JUND, HTR1A, MME 48, 3727, 3350, 4311 275,CG6147,CG2275

,N0TCH1,MMEL1,CCN , 4851, 79258, 595, 1 ,CG7485,CG9565,CG

Dl, CYP3A4,NF2, APC 576, 4771, 324, 3082 3936,CG9565,CG909

, HGF, HSPA4, HSPA5, , 3308, 3309, 5243, 1 6,CG9438,CG14228,

ABCB1, DAB1, PREP 600, 5550 CG6193, CG13744, CG

6603,CG5436,CG387

9,CG9695,CG5355 valsartan PREP 4771 CG14228 B valspodar CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 0 vandetanib KDR, ABCB1 3791, 5243 CG8222, CG3879 0 vapreotide SSTR2, SSTR1 6752, 6751 CG7285, CG7285 0 venlafaxine SSTR1 5550 CG5355 0

Verapamil PLAT , MAPT , VHLL, AB 5327, 4137, 391104, CG13744,CG31057,C B

CB1,CYP3A4,KLHL1 5243, 1576, 57626 G13221,CG3879,CG9

438,CG17754 verlukast ABCB1 , KLHL1 5243, 57626 CG3879, CG17754 0 verrucosidin KLHL1 5327 CG13744 0 versipe- HSPA5 4137 CG31057 B lostatin

VGA1155 KDR, FLT1 3791, 2321 CG8222, CG8222 0

Vigil FLT1 1576 CG9438 0 vincaleu- CYP3A4 57626 CG17754 0 koblastine

vincristine HSPB2,RPSA,EIF2S1 3316, 3921, 1965, 16 CG14207,CG14792,C 0

,TIMM8A,TXNL1,CYP 78, 9352, 1576, 891, G9946,CG1728,CG54

3A4,CCNB1,ABCB1,K 5243, 57626, 3315, 2 95,CG9438,CG3510,

LHL1, HSPB1, FOXD3 7022 CG3879, CG17754, CG

14207, CG3668

Vindesine FOXD3 1678 CG1728 0 vinorelbine GLA, CYP4F3 2717, 4051 CG5731, CG3466 0

Visken CYP4F3 891 CG3510 B Viviq IK 27022 CG3668 B voriconazole CYP3A4,MAPT 1576, 4137 CG9438, CG31057 B vorozole MAPT 4051 CG3466 B vulnibactin SERPINB1 3350 CG7485 O

Wakil FURIN 50846 CG4637 O

Warfarin CYP4F2,CYP3A4,CSE 8529, 1576, 1434 CG3466,CG9438,CG1 B

1L 3281

Wartmannin JUNB, JAK2 , RAC1 , MS 3726, 3717, 5879, 44 CG2275,CG1594,CG2 B

N, GSK3B, JUN, JUND, 78, 2932, 3725, 3727 248,CG10701,CG262

CCNB1, GF2, CYP3A4 , 891, 2247, 1576, 59 1,CG2275,CG2275,C

, CCND1, FGF7 , ETV5 , 5, 2252, 2119, 64689 G3510,CG4608,CG94

GORASP1 , HGF , 3082 38,CG9096,CG4608,

CG6892,CG7809,CG1

3744

WAY 100635 HGF 891 CG3510 B

Wogonin JUND, JUN, JUNB 3727, 3725, 3726 CG2275, CG2275, CG2 B

275

WR 1065 JUNB 2252 CG4608 B

WS 79089B GORASP1 2119 CG6892 O xanthohumol CYP3A4, ABCB1 1576, 5243 CG9438, CG3879 O

Xaxa PLAT, MLH1, JUND, SE 5327, 4292, 3727, 46 CG13744,CG11482,C O

RPINC1, JUN, GORASP 2, 3725, 64689, 595, G2275,CG9456,CG22

1 , CCND1 , JUNB, ABCB 3726, 5243 75,CG7809,CG9096,

1 CG2275, CG3879 ximelagatran ABCB1 4292 CG11482 B

Xylit ABCB1 3727 CG2275 B

Y 27632 JUND, RAC1 , JUNB, JU 3727, 5879, 3726, 37 CG2275,CG2248,CG2 B

N 25 275,CG2275

YM-201627 JUN 3726 CG2275 B

YM-231146 FGF2 5243 CG3879 O zacopride HTR4, (KDR) 3360, (5243) CG6919, (CG3879) O zafirlukast HTR4 5550 CG5355 O

ZD 4190 CYP3A4 3727 CG2275 B zeaxanthin KDR 5879 CG2248 B

Zeldox ABCB1 3726 CG2275 B zileuton CYP3A4 3725 CG2275 B

Zimco JUND, JUN, JUNB 3727, 3725, 3726 CG2275, CG2275, CG2 O

275

zincov ΡΡΑΙ,ΜΜΕ 5464, 4311 CG4634, CG9565 O

ZK 112993 MME 5243 CG3879 O ZM323881 RPSA 1576 CG9438 0 zopiclone KDR 4051 CG3466 B ZSTK474 CYP3A4 3727 CG2275 B Zymosan PSMC1,MBL2 5700, 4153 CG5289, CG7763 B

In preferred embodiments, the present invention is definded as follows :

Definition 1. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.

Definition 2. The method of reducing weight and/or body fat in a subject or to treat obesity comprising the administration of an antagonist of one or more of the genes selected from

CG30184, CG10369, CG32401, CG2374, CG8693, CG14909, CG13299, CG7847, CG30462, CG30462, CG15169, CG1650, CG6577, CG30491, CG4373, CG10407, CG2198, CG6356, CG5744, CG9506, CG31169,

CG1728, CG9220, CG15625, CG5550, CG13088, CG13188, CG14968, CG1503, CG1666, CG14869, CG2702, CG2984, CG4394, CG9922,

CG14529, CG17781, CG17781, CG9153, CG15178, CG5641, CG3879, CG15579, CG1422, CG6299, CG8107, CG7103, CG10617, CG30360,

CG32971, CG32336, CG31036, CG12602, CG9676, CG1433, CGllOO, CG31697, CG7095, CG2165, CG10230, CG10916, CG3274, CG18767, CG5072, CG3396, CG15582, CG16826, CG6788, CG9487, CG1888,

CG4637, CG15162, CG5719, CG2254, CG4695, CG14936, CG17867,

CG15646, CG5402, CG15095, CG8250, CG18030, CG14303, CG14164, CG14677, CG12105, CG17440, CG32459, CG11404, CG8954, CG13138, CG9056, CG12997, CG12997, CG5436, CG14330, CG10809, CG1622, CG3893, CG1112, CG31690, CG12664, CG13679, CG17556, CG10062, CG31744, CG9760, CG1555, CG14375, CG32170, CG4271, CG32234, CG7287, CG14341, CG30486, CG31692, CG31421, CG5467, CG30065, CG9086, CG1688, CG17026, CG4415, CG10343, CG15388, CG13984, CG3313, CG13116, CG4662, CG6919, CG17841, CG30411, CG9053,

CG1180, CG14166, CG13125, CG13344, CG1490, CG2867, CG5591,

CG14362, CG1531, CG15390, CG6689, CG14234, CG14265, CG5674, CG3917, CG8257, CG9028, CG1722, CG18402, CG7082, CG11797,

CG3663, CG16704, CG31172, CG31219, CG1363, CG6721, CG5688,

CG8527, CG13137, CG6612, CG6947, CG7737, CG1705, CG14704,

CG10300, CG3597, CG3425, CG2540, CG6856, CG12259, CG4583,

CG3843, CG9634, CG3809, CG9295, CG9485, CG11555, CG11601,

CG14095, CG10166, CG2852, CG14164, CG14164, CG2898, CG3162, CG6603, CG8721, CG17742, CG14127, CG8665, CG9438, CG32113,

CG32353, CG4957, CG33558, CG11570, CG32669, CG11575, CG30271, CG7830, CG31061, CG2076, CG17596, CG6824, CG17921, CG12875, CG13020, CG13972, CG13673, CG10772, CG8079, CG13127, CG9144, CG8979, CG7097, CG11768, CG10632, CG14903, CG1874, CG33466, CG3367, CG4851, CG17985, CG31229, CG3260, CG13023, CG11125, CG17184, CG31812, CG13360, CG30075, CG30183, CG7485, CG5495, CG5495, CG7065, CG13202, CG7779, CG9322, CG7091, CG16758,

CG5071, CG4920, CG1516, CG9554, CG10101, CG3004, CG7796,

CG10152, CGI 8741, CG8444, CG11425, CG10128, CG10542, CG11878, CG14434, CG12345, CG2091, CG31459, CG13319, CG7177, CG7776, CG15005, CG31605, CG7213, CG17283, CG18268, CG3017, CG7567, CG32091, CG9695, CG8222, CG1515, CG8256, CG1975, CG32467,

CG3817, CG4038, CG6193, CG1572, CG8117, CG3526, CG7099, CG18525, CG9198, CG30470, CG17273, CG31439, CG1387, CG9952, CG6580,

CG10840, CG13221, CG8202, CG8786, CG7199, CG11663, CG12683, CG31161, CG8009, CG17202, CG1683, CG17335, CG33204, CG14694, CG11229, CG16836, CG12209, CG18414, CG13475, CG11621, CG13332, CG11756, CG11133, CG18586, CG4944, CG3213, CG4152, CG6147,

CG8515, CG5827, CG12691, CG8308, CG13807, CG2260, CG30004,

CG4247, CG4247, CG5739, CG4202, CG4264, CG5245, CG13707, CG3523, CG10686, CG9565, CG4111, CG14673, CG31132, CG5355, CG32149, CG8443, CG17461, CG8190, CG13744, CG9258, CG6043, CG1759,

CG8534, CG14792, CG8451, CG8654, CG12806, CG14938, CG9399,

CG10542, CG13168, CG31845, CG6277, CG17819, CG2818, CG1688, CG13868, CG17736, CG7546, CG31693, CG12897, CG2146, CG3440, CG3696, CG12426, CG18319, CG18279, CG18279, CG3054, CG2145, CG3825, CG9781, CG13423, CG12030, CG14911, CG3911, CG6122,

CG7206, CG8566, CG30476, CG9470, CG6127, CG5381, CG12505,

CG1279, CG32140, CG12184, CG31364, CG1963, CG5484, CG4634,

CG9748, CG32442, CG1921, CG18740, CG1242, CG9946, CG11121,

CG3497, CG6817, CG30080, CG1171, CG11430, CG10691, CG13281, CG11352, CG3839, CG14368, CG14024, CG9936, CG11505, CG11906, CG1263, CG14011, CG11339, CG12015, CG30389, CG17331, CG15432, CG15507, CG14842, CG3906, CG17754, CG5289, CG5378, CG5625,

CG6156, CG13243, CG8239, CG1821, CG7762, CG3108, CG8053, CG3605, CG4207, CG8431, CG9098, CG5270, CG5595, CG6064, CG6967, CG7134, CG7549, CG6892, CG10687, CG10712, CG11981, CG12770, CG15599, CG18563, CG7770, CG6322, CG3806, CG3980, CG6054, CG7292, CG3992, CG2998, CG8337, CG13194, CG5147, CG16903, CG11202, CG10084, CG12323, CG31484, CG6949, CG7352, CG10728, CG11376, CG32210, CG7109, CG8615, CG9160, CG8298, CG15115, CG1965, CG12595,

CG15321, CG6009, CG11267, CG4453, CG3971, CG17255, CG32791, CG14016, CG14016, CG1740, CG32667 or an ortholog thereof.

Definition 3. The method according to definition 1 or 2, characterized in that the compound or antagonist is administered in a effective therapeutic dose.

Definition 4. The method of any one of definitions 1 to 3, characterized in that the compound is administered topical, en^¬ teral or parenteral, in particular preferred oral or rectal, in^¬ travenous, intraarterial, intramuscular, subcutaneous, intrader^¬ mal or intraperitoneal, transdermal, transmucosal or inhala- tional .

Definition 5. The method of any one of definitions 1 to 4, characterized in that the subject is mammal, preferably a human.

Definition 6. The method of any one of definitions 1 to 5, characterized in that the compound or antagonist is provided in a medicament.

Definition 7. The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is provided to^¬ gether with a pharmaceutically acceptable carrier or buffer.

Definition 8. The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is administered in a dosage of between 0.01 mg/kg and 1 g/kg.

Definition 9. Use of a compound as defined in definitions 1 or an antagonist as defined in definition 2, preferably further defined as in any one of definitions 3 to 8, for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat or prevent obesity in a subj ect .

Further preferred definitions are given in the claims.

The present invention is further illustrated by the follow^¬ ing figures and examples.

Figures:

Figure 1. Genome-wide RNAi screen for obesity factors in adult Drosophila in vivo .

(A) Schematic of the screen design: virgin heat shock inducible (Hsp70-GAL4 ; Tub-GAL80ts) females were crossed to UAS-RNAi trans- genie males. RNAi was induced 2 days post-eclosure and again af^¬ ter 4 days. One week after RNAi-induction triglyceride and pro^¬ tein levels were determined in a 96-well format and compared to internal controls: non-induced progeny of the same cross. (B) The system was capable of detecting developmental and sex- specific fat storage patterns, and (C) a variety of fedding con^¬ ditions. Data are shown as mean triglyceride content +/- sem. n=8. (D,E) Double blinded retrieval of primary screen results for positive control lines predicted to (D) reduce or (E) in^¬ crease triglyceride levels. (F) Z-score distribution of the pri^¬ mary screen results. Red lines indicate Z-scores of +1.65 above and -1.65 below baseline levels. (G) Gene ontology analysis with a level 5 cut-off for biological processes for all annotated genes with Z-scores above or below ±1.65 after three rounds of testing. See also Figs. 2 and 4.

Figure 2. Basal triglyceride and protein contents in Drosophila . Related to Figure 1.

(A) Triglyceride content of wlll8 Drosophila strain measured throughout development using a medium-throughput 96-well plate based system with a colorimetric determination endpoint. (B) Protein content of wlll8 Drosophila measured with the same ex^¬ perimental set-up. Data in a and b are shown as mean triglyc^¬ eride content +/- s.e.m. n=5-8. (C) Individual triglyceride and protein content in 80 different sets of 8 male flies each meas^¬ ured 2 to 4 days after eclosure. Measurement was made to vali^¬ date the medium throughput experimental system designed for the genome-wide screen. (D) Pie chart summarizing the most depleted functional classifications using gene ontology for biological processes for all annotated genes with Z-scores in excess of +/- 1.65 through three rounds of testing.

Figure 3. Tissue-specific regulation of fat storage.

(A) Heat-map of changes in triglyceride for primary screen hits crossed to nsyb-GAL4 (pan-neuronal ) , oe-GAL4 (oenocyte) , C57- GAL4 (muscle), and ppl-GAL4 (fat-body) drivers. Changes are relative to control RNAi-lines and isogenic wlll8 flies crossed to the respective GAL4 drivers. (B-E) Left panels show the mean changes in triglycerides after tissue-specific knockdown for the top-scoring fat-enhancing (red lines) and fat-depleting (blue lines) genes in each tissue category. Note the marked neuronal specificity, an overlap in fat-body and oenocyte responses, and a relative lack of specificity for top-scoring muscle responsive genes. Right panels summarize gene-ontology analysis for each category (level 5 cut-off for biological processes) . Intensity of the red reflects increased significance of the GO term.

Figure 4. Interaction network for candidate obesity genes . Related to Figure 1.

The interaction network was assembled using Cytoscape 2.6.2 based on interactions retrieved from STRING, DROIDB, and BI- OGRID. Datasets consisted of yeast-2-hybrid, text-mining, and database annotations (e.g. KEGG) . Assembly of the visual layout was performed using manual modification of an automated force- directed layout. Insets highlight the location of both the hedgehog and insulin signaling pathways.

Figure 5. Analysis of tissue-specificity reveals hedgehog signaling as a fat-body specific regulator of triglyceride levels .

Triglyceride responses of candidate genes. Changes in adiposity in RNAi lines with the most tissue-restricted responses in the (A) pan-neuronal , (B) muscle, (C) oenocyte, and (D) fat-body compartments. (E) Heat-map of adiposity observed in UAS-RNAi transgenic fly lines targeting available annotated hedgehog and notch pathways. Changes are relative to averages of control RNAi-lines and wlll8 flies crossed to the respective GAL4 driv^¬ ers. Genes are grouped according to their role as either posi^¬ tive (+) or negative (-) effectors, or as mediators of ligand processing and release (Lp) . (F) Representative triglyceride changes in response to ppl-GAL4 driven knockdown of effectors of hedgehog signaling and (G) repressors of the pathway. Data are presented as mean ± s.e.m., n = 4. * p<0.05. See also Fig. 6.

Figure 6. Tissue-specificity of hedgehog and OxPhos pathway triglyceride changes . Related to Figure 5.

(A) Correlation analysis of triglyceride levels in RNAi lines targeting hedgehog signaling crossed to the tissue-specific drivers nsyb-GAL4 (pan-neuronal) , oe-GAL4 (oenocyte) , C57-GAL4

(muscle) , and ppl-GAL4 (fat-body) . Tissue-specific triglyceride changes (y-axes) are correlated with those observed using the inducible ubiquitous Hsp70-GAL4 ; ub-GAL80ts (x-axis) . (B)

Triglyceride changes in ppl-GAL4 driven UAS-RNAi transgenic lines targeting hedgehog specific ligand processing and release genes. (C) Heat-map of the adiposity of UAS-RNAi transgenic fly lines targeting the members of the gene ontology category oxida^¬ tive phosphorylation. Changes in adiposity were in response to tissue-specific silencing using the drivers nsyb-GAL4 (pan- neuronal) , oe-GAL4 (oenocyte) , C57-GAL4 (muscle) , and ppl-GAL4 (fat-body) . Changes are relative to averages of control RNAi- lines and wlll8 flies crossed to the respective GAL4 lines. (D) Triglyceride responses of the same oxidative phosphorylation targeting RNAi-transgenic lines to heat-shock induced ubiquitous knockdown. Data are presented as mean ± s.e.m. n=4.

Figure 7. aP2-Sufu mice display white adipose tissue specific lipoatrophy .

(A) aP2-SufuKO mice are born healthy and at Mendelian ratios.

(B) NMR imaging of an aP2-SufuKO mouse and a Sufu-expressing littermate control. (C) Cross-section at the level of the scapu^¬ lae show unaltered brown adipose depots (yellow dashed lines) .

(D) PCR revealed robust deletion of the Sufu allele (Sufu 4-8) in both BAT and WAT depots. Minor deletion was detected in skeletal muscle, lung, and the spleen. (E) Tissue dissection white adipose tissue (WAT; upper panel) and brown adipose tissue

(BAT; lower panel) revealed fully developed brown adipose depots despite severely compromised white adipose tissue depots in aP2- SufuKO mice. Dashed lines mark white adipose tissue. (F,G) Rep^¬ resentative H&E stained sections of (F) brown (BAT) and (G) white (WAT) adipose tissues from aP2-SufuKO and control litter^¬ mate mice. (H,I) Quantitative RT-PCR of the transcriptional hedgehog targets Glil, Gli2, Ptchl and Ptch2 confirmed activa^¬ tion of hedgehog signaling in both (H) WAT and (I) BAT of aP2- SufuKO mice relative to targeted (flox) and aP2-cre (ere) trans^¬ genic littermate controls. Data are presented as mean ± s.e.m. n = 5 mice per group. * p<0.05. See also Fig. 8.

Figure 8. IBMX and dexamethasone dependence of hedgehog signaling in adipocytes and generation of lipoatrophic Sufu mutant mice . Related to Figure 7.

(A) Oil Red 0 staining of 3T3-L1 cells induced with minimal (In- sulin/Troglitazone) or complete ( Insulin/Troglitazone/IBMX/Dex) differentiation cocktails in the absence (control) or presence

(SAG) of the hedgehog agonist SAG (200nM) . One experiment repre^¬ sentative of 5 repeats is shown. (B) Quantitative RT-PCR moni^¬ toring of hedgehog pathway activation with the target genes Glil and Ptchl confirmed activation by SAG and abrogation of hedgehog induction in the presence IBMX and Dex. (C) To establish an in vivo model to assess hedgehog effects on adipose biology, a tar^¬ geting strategy was used to generate mice with a conditional Sufu allele. The conditional allele encorporates two Cre- sensitive loxP sites flanking exons 4-8 of the Sufu open reading frame. Numbered boxes indicate exons. (D) White (perigonadal ) adipose tissue, interscapular brown adipose tissue and muscle

(soleus and gastrocnemius) masses were determined in aP2-SufuKO mice at 8 weeks of age. Data from littermates that carry the floxed allele (flox) or aP2-Cre (ere) are shown as controls. Data are presented as mean ± s.e.m. n = 6 mice per group. ** p<0.01. (E) H&E stained sections of skin highlight a clear re^¬ duction in cutaneous adipose tissue. (F) White adipocyte size distributions in perigonadal fat pads taken from 4 week old male aP2-SufuKO mice and littermate floxed (flox) and aP2-Cre (ere) controls. Measurements were made by morphometry on >10,000 (KO) and >35,000 (controls) cells per animal using a combination of scanning of H&E stained interval sectioned adipose tissue (3 per mouse) and subsequent software assisted morphometric analysis

(G) Total white adipocyte cell numbers in 4-8 week old male aP2- SufuKO mice and littermate floxed (flox) and aP2-Cre (ere) con^¬ trols. Data are presented as mean ± s.e.m, n=5.

Fig 9. Loss of weight in Vandetanib administered mice. C57BL6/J DIO mice were administered 40/mg/kg/day by oral gavage . The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1) . By day 13 of administration there was significant loss of weight in the vandetanib adminis^¬ tered group compared to the vehicle control (p < 0.05; unpaired student t test) which was maintained for the duration of the ex^¬ periment. Error bars represent standard error of the mean.

Fig 10. Lower fasting glucose levels in vandetanib administered mice. On day 7 of vandetanib administration the mice were sub- jected to an Insulin Tolerance Test. Briefly the mice were fasted for 2 hours. Blood was collected at time 0 prior to in^¬ jection of insulin. Blood was collected at 15, 30, 45 and 60 minutes after injection to measure the glucose response. Al^¬ though the insulin response was similar in both groups, the vandetanib administered mice exhibited lower fasting blood glu^¬ cose levels compared to the controls (p < 0.05; unpaired stu^¬ dent t test) . Error bars represent standard error of the mean.

Fig 11. Oral glucose tolerance test (oGTT) in vandetanib administered mice compared to vehicle controls. Mice were fasted overnight and on day 35 a blood sample was taken to measure the fasting glucose levels (time 0) . The mice were administered glu^¬ cose, blood was collected and the glucose levels were measured 15, 45 and 60 minutes after glucose administration. Vandetanib administered mice show an improved glucose response compared to the vehicle administered group 15, 45 and 60 minutes after glu^¬ cose administration (p < 0.05; unpaired student t test) . Error bars represent standard error of the mean.

Fig 12. Measurement of perigonadal fat pad weights . The

vandetanib and vehicle administered mice were sacrificed on day 38 of administration. The perigonadal fat pads were dissected and the weight (grams) was expressed as a ratio compared to body length (cm) . Each point on the graph represents the average weight (g) of the two perigonadal fat pads from each mouse ex^¬ pressed as a ratio to body length (cm) . The vandetanib adminis^¬ tered mice have a proportionally lower fat pad mass compared to vehicle controls (p < 0.05; unpaired student t test) . Error bars represent standard error of the mean.

Fig 13. Loss of weight in dasatininb administered mice. C57BL6/J DIO mice were administered 5/mg/kg/day for 27 days. The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1) . On day 28 there was significant loss of weight in the dasatinib administered group compared to the vehicle control (p < 0.001; unpaired student t test) . Error bars represent standard error of the mean.

Fig 14. Improved insulin response in dasatinib administered mice on day 15 of administration. An oral glucose tolerance test

(oGTT)was performed in mice which were fasted overnight. A blood sample was taken to measure the fasting glucose levels (time 0) . The mice were administered glucose, blood was collected and the glucose levels measured 15, 30, 45 and 60 minutes after glucose administration. Dasatinib administered mice show an improved early response to glucose administration at the 15 minute (p < 0.01), 30 and 45 minute (p < 0.05) time point compared to the vehicle administered group. Error bars represent standard error of the mean.

Fig 15. Improved insulin response in dasatinib administered mice on day 29. An oral glucose tolerance test (oGTT)was performed in mice which were fasted overnight. A blood sample was taken to measure the fasting glucose levels (time 0) . The mice were ad^¬ ministered glucose, blood was collected and the glucose levels measured 15, 45 and 60 minutes after glucose administration. The values obtained for each mouse was expressed as percentage of the starting glucose levels (t = 0) . Dasatinib administered mice show improved glucose clearance 45 (p < 0.05) and 60 minutes (p < 0.01) after glucose administration compared to the vehicle ad^¬ ministered group (Student t-test; p < 0.05) . Error bars repre^¬ sent standard error of the mean.

Examples :

Example 1 : in vivo high throughput screen for obesity genes in Drosophila

To identify candidate obesity genes, we performed a genome- wide RNAi transgenic-RNAi screen for fat content in adult Drosophila using a heat shock-inducible Hsp70-GAL4 system (Fig. 1A) . Triglycerides, the major lipid storage form in animals, were chosen as a direct measure of fly adiposity. Total fly triglyc^¬ eride levels were measured by colorimetric determination and normalized to protein (Fig. 1A) . Using this experimental set-up, we were able to track triglyceride changes throughout develop^¬ ment as well as to clearly distinguish sex-specific differences in fat content (Fig IB; Fig. 2A,B) and those induced by varying nutrient availability (Fig. 1C) . After the first round of screening, double-blinded analysis of RNAi lines targeting genes previously reported to regulate fat content revealed lipid al^¬ terations consistent with expected lean (Fig. ID) and obese (Fig. IE) phenotypes. Included were the LSD (Lipid Storage Drop^¬ let) and LPD (LiPid Depleted) genes as well as the Drosophila insulin like peptides (Hp's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp) , bubblegum (bbg) , and the Drosophila SREBP homologue, HLH106 (Gronke et al . , 2007; Hader et al . , 2003; Min and Benzer, 1999).

Example 1.1: genome-wide obesity screen in adult Drosophila

We tested the fat regulatory potential of 11,594 different UAS- RNAi transgenic lines corresponding to 10,812 transgene constructs and 10,489 distinct ORFs, in the adult fly. Primary screening involved three rounds of testing where candidates with a Z-score greater than 1.65 were selected for retesting (Fig. 1A, F) . After three rounds of selection 516 RNAi-transgenic lines remained, 462 of which had only single primary target predic^¬ tions (S19 score ≥0.8 and ≤6 CAN repeats as described by (Dietzl et al . , 2007) . Important for the translation of these findings into the mammalian context, 319 of 516 (62%) have human orthologues according to InParanoid, OrthoMCL, and Ensembl data^¬ bases .

Gene ontology (GO) based pathway analysis for biological process revealed enrichment of gene sets involved in cell fate determi^¬ nation, cellular protein metabolic processes, signal transduc^¬ tion, intracellular transport, and regulation of smoothened sig^¬ naling. Pathways most depleted during the screen, i.e. those not relevant to fat regulation, included genes regulating behavior, cell cycle, organelle organization and biogenesis, locomotory behavior, and chromosome organization. A network interaction assembly based on yeast-2-hybrid, text-mining, and pathway data^¬ base information on the Drosophila hits and their mammalian orthologues revealed an interaction network map (Fig. 4) highlighting genes of development, nutrient transport, cell cycle regulation, the proteasome, protein translation, and chromatin remodeling. Of particular interest, the candidate gene list in^¬ cluded a number of potential regulators of feeding control. For instance, six odorant and two gustatory receptor genes were tar^¬ geted (Odorant receptorslOa, 56a, 65a, 67a, 83cd, and CG10407; gustatory receptors 98b and 36b) . Also, the dopamine receptor DopR2, two octopamine receptors (TyrR and oa2) and the Nmda- receptor associated protein Nmdal all showed reduced body fat content following RNAi induction. In addition, altered fat deposition was observed in response to RNAi knockdown of known me^¬ diators of glucose/lipid mobilization including fructose-1 , 6- bisphosphatase (fbp) , the two members of the glycerol phosphate shuttle (CG31169 and Gpo-1) , mitochondrial acyl-carrier protein 1 (mtacpl) , ADP/ATP translocase 2 (Ant2) , pyruvate carboxykinae

(CG1516), and fatty-acid synthetase (fasn) . Also identified were the Drosophila orthologues of glucagon (akh) , the insulin recep^¬ tor (dlnR) , as well as the downstream kinases PI3-kinase

(dPI3K) , ribosomal-S6-kinase ( dRSK) , the CREB-coactivator dTORC, and the critical TOR-signaling constituent dTSC-1,

Drosophila homologues of the critical early adipogenic regula^¬ tors NCORl/2, Jagl/2, and TAK1 (Ross et al . , 2004; Suzawa et al . , 2003; Yu et al . , 2005), or the metabolic regulators CRTCl/2 and pyruvate carboxylase (PC) (Altarejos et al . , 2008; Koo et al . , 2005; Zhang et al . , 1995) . We also hit the Drosophila lipo^¬ protein rfabg (retinol fatty-acid binding glycoprotein) previously shown to transport key developmental morphogens such as hedgehog (Panakova, 2005) . Indeed, "regulation of smoothened [hedgehog] signaling" was the most highly enriched signal trans^¬ duction pathway in our gene-ontology analysis (Fig. 1G) . Thus, our genome-wide approach identified multiple known molecular players previously associated with adipocyte development and function. Most importantly, the screen revealed a large number of candidate genes not previously associated with obesity.

Example 1.2: Tissue specific mapping of candidate obesity genes

Considering the complexity of metabolism and the recognized di^¬ versity of tissue-specific processes that govern lipid-storage (Leopold and Perrimon, 2007; Speakman et al . , 2008), we set out to functionally categorize the candidate lipid regulators ac^¬ cording to tissue-specificity. RNAi-lines of the 462 primary screen candidate genes were crossed to four independent GAL4 drivers with pan-neuronal (nsyb-GKL ) , muscle (C57-GAL4 , oeno- cyte (oe-GAL4 , and fat-body (ppl -GAL4) specificity, and their respective triglyceride levels determined (Fig. 3A) . Interest^¬ ingly, RNAi lines most strongly regulating fat-content after pan-neuronal {nsyb-GKL ) knockdown elicited little or no change in fly triglyceride levels when induced in the muscle, oenocyte or fat body (Fig. 3B) . Muscle-specific gene silencing (C57- GAL4), by contrast, enriched for genes that also elicited sig^¬ nificant changes in triglycerides when targeted in oenocytes and the fat-body (Fig. 3C) . RNAi-lines responding most substantially to oenocyte and fat-body specific knockdown displayed a coordi^¬ nate and reciprocal pattern of adiposity regulation (Fig. 3D and 3E) ; these findings are in keeping with the tight regulatory interplay reported for these correlates of the mammalian adipose and liver (Gutierrez et al . , 2007) . GO analysis of the combined fat-enhancing and fat-diminishing gene sets for each of the four tissues tested are summarized in Fig. 3B-E. In support of the inducible design of the current screen, cell fate, cell differ^¬ entiation and organ development pathways showed strong enrich^¬ ment in the analysis (Figure 3B-E, right panels: The neuronal hits (nsyb-GKL ) are: CG5436, CG2091, CG17461, CG11339, CG11202 CG5245, CG14911, CG30075, CG16836, CG5147, CG17184, CG10728

CG17742, CG4851, CG5381, CG18563, CG18268, CG10542, CG12015 CG4152, CG32669, CG32149, CG11756, CG12691, CG12595, CG32210 CG1279, CG17255, CG2260, CG14024, CG2146, CG7776, CG31132 CG3497, CG9936, CG10152, CG14842, CG6043, CG8515, CG9946 CG17819, CG11125, CG2145, CG12030, CG1759, CG1921, CG14303 CG6603, CG3906, CG30271, CG18740, CG12505, CG13202, CG8451 CG15507, CG6817, CG2818, CG12105, CG13423, CG32667, CG18586 CG17736, CG11376, CG11430, CG2898, CG4957, CG3054, CG12345 CG18414, CG14673, CG2254, CG32442, CG6122, CG13360, CG8298 CG6147, CG13319, CG33558, CG5625, CG13679, CG12806, CG3806 CG6064, CG15095, CG10691, CG3971, CG11505, CG3017, CG3108 CG3992, CG17754, CG14164, CG13332, CG3839, CG8443, CG7065 CG10632, CG1516, CG4247, CG4247, CG3004, CG31845, CG31744 CG9028, CG16826, CG13137, CG7082, CG6299, CG32091, CG30184 CG30491, CG11768, CG14968, CG17921, CG4415, CG5072, CG7199 CG4373, CG30411, CG14166, CG1555, CG2198, CG6947, CG6824 CG8079, CG1888, CG9295, CG14903, CG10617, CG10230, CG17781 CG17781, CG6721, CG7103, CG32170, CG3526, CG7737, CG11601 CG32336, CG1975, CG14909, CG11797, CG9922, CG11555, CG30470 CG17841, CG9153, CG31172, CG17335, CG7287, CG3396, CG13116 CG13984, CG33466, CG30065, CG14265, CG32234. CG2076, CG4038 CG14704, CG9053, CG30486, CG31219, CG1171, CG10840, CG6577 CG7099, CG1433, CG13673; The muscle (C57--GAL4 ) hits are:

CG11339, CG18740, CG11376, CG7206, CG4583, CG12015, CG32667,

CG14011, CGI 4024, CGI 1601, CG9634, CG12505, CG9695, CG14911,

CG30486, CG12595, CG17754, , CG9936, CG6009, CGI 705, CG30080,

CG32210, CG3817, CG8202, CGI 8268, CG31421, CG31692, CG31605,

CG9748, CG14434, CG31161, CG12806, CG6947, CG3054, CG12770,

CG6127, CG11505, CGI 963, CG11555, CG5147, CG13319, CG4634,

CGI 1819, CG32091, CG9160, CGI 8279, CGI 8279, CG32467, CG8337,

CG8239, CG12259, CG3911, CG8654, CG1279, CG32140, CG7776,

CG6892, CG13984, CG2091, CGI 7026, CG33204, CG11121, CG3497,

CG6122, CGI 5321, CG6949, CG14375, CG10687, CGI 7283, CG14903,

CGI 0101, CG14677, CG7830, CG9056, CG32459, CG2254, CGI 422,

CGI 7867, CG17781, CG17781, CG4373, CG3879, CGI 1756, CGI 0916,

CG10809, CG15390, CGI 4265 CG9322, CGI 650, CG6299, CG5550,

CG2260, CG11570, CGI 0369, CG16836, CG30075, CG2076, CG3213,

CG9220, CG31132, CGI 3868, CG1180, CG14166, CG14095, CG13127,

CG31061, CG14362, CG32401 CG7796, CGI 728, CG9506, CG3260,

CGI 5625, CG7779, CG8107, CG30411, CG7103, CG7485, CG9676,

CG3809, CG2702, CGI 5646, CGI 3972, CG14968, CG12664, CG12997,

CG12997, CG4957, CG14869, CG3274, CG5719, CG5591, CG11133,

CG7847, CG11768, CG8721, CG9258, CG5674, CGI 7184, CG13673,

CGI 7461, CGI 1404, CGI 622, CG9554, CG13707, CG13344, CG4264,

CG10772, CGI 3360; The oenocyte hits ( oe-GAL4 ) are: CG12505,

CG33204, CG4207, CG15507, CGI 683, CG32353, CGI 7461, CG11202,

CG15432, CG9198, CG9295, CG1490, CG7830, CG31161, CG9028,

CG3497, CGI 4265, CG4944, CG11229, CG11376, CG3825, CG31484,

CG32210, CGI 705, CG11339, CG11133, CG3806, CG3971, CG13807,

CG18414, CGI 0166, CG12015, CG6127, CG14234, CG12595, CG17596,

CG7292, CG2898, CG32091, CG17754, CG5625, CGI 0632, CG9634,

CG2145, CG10084, CGI 0728, CG3526, CG6967, CG5270, CG15115,

CG3425, CG9485, CG13707, CG8009, CG9160, CG33558, CG6892,

CGI 4024, CG6689, CG3906, CG8079, CGI 874, CGI 516, CG5674,

CG12184, CG2852, CG9438, CG6054, CGI 7921 , CG15599, CG8202,

CG33466, CG14362, CG2540, CG7352, CG9695, CGI 572, CG13319,

CG3313, CG13188, CG13137, CG31744, CG30360, CG3893, CG5436,

CG3696, CG4851, CG7287, CGI 0916, CG8527, CG14909, CG3004,

CG7213, CGI 422, CG9760, CG30486, CG32234, CG13088, CG3440,

CG4373, CG7485, CG14936, CG11425, CGI 0152, CG12345, CG15582,

CGI 5646, CG8693, CGI 1404, CGI 5625, CG11125, CG2374, CG14677,

CG2702, CG32401, CG9676, CGI 622, CG13299, CG8107, CG31421, CG3879, CG5719, CG7737, CG4271, CG13168, CG31692, CG10101, CG17867, CG16758, CG32170, CG7796, CG5641, CG10369, CG17283, CG30184, CG9220, CG3017, CG30462, CG30462, CG31605, CG14968, CG12664, CG6299, CG2984, CG14341, CG8250 , CG9399, CG3809, CG9506, CG8444, CG2818, CG31812, CG7103, CG3523, CG30065; and the fat-body hits (ppl -GAL4) are: CGI 7461, CG15432, CG11339 CG32091, CG9565, CG3839, CG13972, CG30183, CG6721, CG14011

CG13243, CG12323, CG5245, CG11267, CG8515, CG32210, CG8654

CG2260, CG3274, CG9554, CG31845, CG8337, CG8190, CG6788

CG11376, CG3497, CG11229, CG17754, CG31697, CG32467, CG18402

CG2146, CG3523, CG30470, CG30075, CG1975, CG4264, CG32442

CG9322, CG9160, CG10632, CG16836, CG6949, CG6147, CG8079

CG3817, CG5595, CG12806, CG3980, CG16903, CG9487, CG7099

CG13744, CG11133, CG3992, CG9952, CG12875, CG7091, CG3440

CG6156, CG4038, CG32791, CG31484, CG1433, CG10687, CG5625

CG9258, CG6892, CG7776, CG31812, CG30080, CG7199, CG17331

CG6277, CG14016, CG14016, CG1874, CG5071, CG9144, CG12015

CG13332, CG32667, CG1888, CG33466, CG12602, CG31693, CG6580

CG12595, CG9056, CG7779, CG7796, CG5495, CG8298, CG15115

CG3260, CG17985, CG8534, CG4202, CG3108, CG3906, CG6054, CG3971

CG7830, CG5688, CG13868, CG7292, CG18767, CG14434, CG12184

CG11621, CG6356, CG9086, CG15646, CG10542, CG6689, CG3425

CG7206, CG11575, CG5719, CG32669, CG15579, CG1722, CG7287

CG4394, CG9220, CG14164, CG14164, CG14164, CG14704, CG3809

CG15169, CG11570, CG18319, CG31690, CG1531, CG7847, CG31692

CG4583, CG13088, CG8566, CG8107, CG32971, CG31421, CG3054

CG15390, CG14869, CG8444, CG30476, CG3879, CG2145, CG3017

CG10809, CG32459, CG14166, CG14936, CG4957, CG14095, CG8665

CG13984, CG13188, CG17841, CG32170, CG12105, CG14968, CG5381

CG18268, CG13299, CG17781, CG17781, CG4271, CG5641, CG8693

CG32140, CG32353, CG30065, CG14909, CG3893, CG6577, CG10152

CG17867, CG13116, CG3843, CG9153, CG30184, CG2984, CG1180

CG14341, CG11404, CG1622, CG32234, CG9506, CG4373, CG2374

CG12997, CG12997, CG13423, CG1963, CG5674, CG14362, CG13344

CG8250. Thus, we provide functional annotation of -500 candidate obesity genes in four key metabolic tissues in Drosophila .

Example 1.3: Neuronal hits

In mammals, the leptin/AgRP/POMC axis exemplifies the profound neuronal dependency of feeding behaviour, metabolic rate, insu- lin resistance and thus, of obesity risk. Flies do not possess known homologues to this axis but their feeding behavior is also neuronally anchored. Approximately one third of the primary screen hit list elicited triglyceride changes >25% when crossed with the neuronal nsyfo-GAL4 driver. A select number exhibited tight neuronal restriction in their response (Fig. 5A) . Included was the Drosophila homologue for SLC5A8 (CG8451; Fig 5A) a neu^¬ ronal fatty-acid and lactate transporter. In rodents, fatty ac^¬ ids are sensed by neuronal processing of lactate generated by adjacent glial cells. Similarly, lines targeting homologues of glucagon (akh, neuronally secreted in Drosophila) , and the neu^¬ ronal Zn-transporter SLC39A10 both displayed tight neuronal re^¬ sponses. Also, TSC1 (o!TSCl) , a critical regulator of the amino acid responsive TOR-signaling pathway, showed marked neuronal and fat-body specific responsiveness (Fig. 5D) . It is likely that aside from peripheral regulation of nutrient storage, TOR signaling in the CNS might relay amino acid status to feeding behaviour. Additional neuronal responsive targets likely to play a direct role in nutrient sensing included the odorant / gusta^¬ tory receptors Obp56a and TyR. Thus, similar to mammals, fat storage in Drosophila appears regulated by a complex network of neuronal genes.

Example 1.4: Muscle hits

Several genes showed tight muscle-specificity (Fig. 5B) , includ^¬ ing homologues of the proline biosynthetic PYCR1 (P5cr) , the glycogen debranching enzyme AGL (CG9485) , and the fbp (fructose- 1 , 6-bisphosphatase) , a key regulator of glycolysis. Mevalonate decarboxylase (CG8239) , which supports cholesterol biosynthesis and is currently being tested therapeutically to reduce choles^¬ terol levels, showed similar muscle-specificity as did the sterol regulating enzyme ARV1 (CG32442) . Mutants of ARV1 have previously been shown to exhibit altered lipid metabolism. In^¬ terestingly, genes involved in TLR-signaling (IM10) , the ribo- some and protein translation (CG3213) , proteolysis (Furl), transcriptional regulation (CG5591) , and microRNA mediated silencing (Smg5) (Fig. 5B) were also found to regulate triglyceride level specifically in muscle cells.

Example 1.5: Fat and oenocyte candidate genes The largest number of primary screen hits showed oenocyte- (oe- GAL4) and fat-body- (ppl -GAL4) responses (Fig. 5C,D). Interest^¬ ing targets included homologues of inflammation-related genes: ARID2 (regulates interferon responsive genes (Yan et al . , 2005), dTraf (fly Traf-like protein) , the pattern recognition receptor PGLYRP2, the interleukin enhancer binding factor ILF2, the extracellular matrix protein tenascin (TNC) , the ubiquitin- conjugating enzyme UBE2N (critical for TNF- and Toll-like- receptor signaling), or the de-ubiquitinating enzyme USP7. Additional components of the ubiquitin-ligase machinery were also revealed, namely UBR2, HERC4, and FBWX5 (also controls TSC1 and thus TOR-signaling) . Together these data support roles for immune regulatory networks and ubiquitination in fat storage regu^¬ lation in Drosophila.

Oenocyte- and fat body-specific knockdown analyses also identi^¬ fied genes involved in glycerol and lipid metabolism (Fig. 5C,D) . For instance, genes related to insulin signaling includ^¬ ing the homologues of PP1 (inhibitory subunit 15b), S6KII, EIF2B, PI3K, and the insulin receptor itself (IR) . Also, direct mediators of lipid and glucose metabolism were identified, such as homologues of the ADP/ATP symporter ANT, NDUFAB1, GDPD, and GPD2. The latter, part of the glycerol-phosphate shuttle, regu^¬ lates glycolytic rate and ROS production. Of interest, mice lacking GPD2 exhibit a 40% reduction in white adipose mass

(Brown et al . , 2002) and share a number of phenotypic features with deficiencies of glycerol kinase (GK) , another enzyme found using the oenocyte-specific driver. In addition, we found T3dh

(an iron-dependent regulator of fatty acid and ketone body me^¬ tabolism) , Cyp6a2 (cytochrome P450 proteins catalyze numerous steps of cholesterol, steroids and lipids synthesis) , and par^¬ ticularly robust in both the oenocyte- and fat-body analyses, the Drosophila homologue of the fatty acid elongase ELOVL6. Elovl6^~/~ mice develop marked obesity and hepatosteatosis and show protection from hyperinsulinemia, hyperglycemia, and hyper- leptinemia (Matsuzaka et al . , 2007). Using fat-body specific knockdown we also hit the Drosophila homologue of ELOVL7. Per^¬ haps most importantly, we found multiple previously uncharacter- ized genes that regulate fat content in an oenocyte- and/or fat body-dependent manner (Fig. 5C,D) . Thus, our screen has revealed a large number of general and tissue specific candidate fly genes and multiple pathways that control triglyceride storage levels .

Example 2 : Mouse in vivo pathway modulation

The biological process "regulation of smoothened [hedgehog] signaling" was one of the most prominent signal transduction pathway of all pathways in the primary screen. An additional 8 potential hedgehog signalling members recently identified in a Drosophila S2 cell screen for modulators of hedgehog signalling

(Nybakken et al . , 2005) were also hit in our primary obesity screen. Together these represent a >20-fold enrichment for the hedgehog signaling pathway. Importantly, hedgehog signaling scored third in fat-body-responsive pathways while not scoring at all in muscle or neuronal datasets (Fig. 5E; Fig. 6A) . Hedge^¬ hog modulation has been suggested previously as a target for obesity therapies (Suh et al . Cell Metabolism, 2006; WO2000/51628) . We therefore homed into the hedgehog pathway to provide proof of principle for the fly screen and to translate our Drosophila results directly into the mammalian context.

To assess the in vivo relevance of the drosophila screen re^¬ sults, hedgehog signaling in mammalian adipogenesis was further investigated. Fat-specific Sufu knockout animals (aP2-SufuKO) were generated (Fig. 8C) . Sufu is a potent endogenous inhibitor of hedgehog signaling in mammals. Suf_u ^flox/flox mice were crossed to the adipose-tissue deleting aP2-Cre transgenic line (Fig. 8C) and the resulting aP2-SufuKO animals were born healthy and at Mendelian ratios. PCR amplification revealed target deletion in both white (WAT) and brown (BAT) adipose tissue (Fig. 7A, D) . aP2-SufuKO mice displayed an immediate and obvious lean pheno- type. MRI analysis revealed a significant and global reduction in white adipose tissue mass, including subcutaneous, perigo- nadal, and mesenteric depots (Fig. 7B) . Intriguingly though, in contrast to the gross loss of WAT, cross-sectional examination of the interscapular region revealed fully developed BAT depots of both normal size and lipid content (Fig. 7B,C) . Direct meas^¬ urement of WAT and BAT depot weights corroborated the divergent WAT / BAT phenotype, with reduction in perigonadal fat pad mass in aP2-SufuK0 mice concomitant with unaltered BAT mass

(Fig. 7E, Fig. 8D) . Tissue weight and histological analyses con- firmed lack of any remarkable phenotype in multiple other tis^¬ sues including pancreas and liver (no indication of steatosis) , and muscle mass was unaffected (Fig. 8D) . Cutaneous adipose was also markedly diminished (Fig. 8E) . Whereas the morphology of Sufu-deficient BAT depots was largely indistinguishable from that of control animals (Fig. 7E,F), examination of multiple WAT pads revealed marked and significant reductions in both adipo^¬ cyte size (Fig. 7E,G; Fig. 8F) and total numbers (Fig. 8G) in mutant animals. Of note, qPCR showed elevated Glil, Gli2, and Ptch2 expression in both WAT (Fig. 7H) and BAT (Fig. 71), verifying the intended pathway activation in both tissues. Thus, de^¬ letion of Sufu in fat tissue results in a markedly decreased white fat cell number and, remarkably, in normal brown adipose tissue. These results demonstrate that hedgehog activation re^¬ sults in a virtually complete block of WAT development but leaves the differentiation process of brown adipocytes wholly intact .

Example 3: Testing of active compounds

General preferred layout: The mice were divided into cages of 2- 4 mice per cage and allowed to acclimatise to the new housing conditions for at least 2 weeks. The mice were weighed every week to monitor their weight and ensure that the mice are either gaining weight or stabilized prior to initiation of the experiment. Mice were randomly assigned to weight-matched groups for compound administration. Compound dosage and routes of admini^¬ stration were determined based on published literature and phar^¬ macokinetic studies.

To test the positive candidates in mice the following protocol was used: JAX^® DIO B6 mice, 18 weeks of age, were divided into groups of 2-4 mice of equivalent body weight upon receipt from Jax labs. The Jax labs protocol for feeding and care of diet- induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet^® 5k52) . At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to in^¬ duce obesity (Research Diets, Inc. D12492i, 60 kcal% fat) . Mice have ad libitum access to food and water. Upon receipt of the animals from Jax labs, animals were kept under similar housing and feeding conditions to those at Jax labs ie. mice continued to receive a high fat diet (Test Diet^® 58Y1 60% energy from Fat) .

In special methods following protocol was used: Modulator com^¬ pounds of the new identified genes responsible for triglyceride or fat regulation underwent two rounds of testing. The first round screened all candidate compounds in Drosophila, and posi^¬ tive candidates were subsequently tested in mice induced to be obese through administration of a high fat diet. Two day old W1118 male Drosophila melanogaster were sorted 20 flies per vial and placed for one week on normal fly food in the presence or absence of each test compound. Test compounds were added to the surface of the fly food in liquid form and allowed to absorb into the top-most layer at 3 doses 0.001 umol/kg/day, 1

umol/kg/day, and 1000 umol/kg/day.

After one week of treatment flies were shock-heated to dry^¬ ness, and dry weight used as an indicator of adiposity. All flies with dry weights <75% of the mean value of control vials were considered positive candidates with obesity lowering activ^¬ ity. Those positive candidates which induced obvious behavioural impairment were removed from the group of positive candidates. Behavioural tests included tapping of the vial (flies should jump into flight) and exposure to light (flies should move to^¬ wards a light source) . All remaining positive candidates were taken forward for analysis in mice.

To test the positive candidates in mice the following proto^¬ col was used: JAX^® DIO B6 mice, 12 weeks of age, were divided into groups of 8-10 mice of equivalent body weight upon receipt from Jax labs. The Jax labs protocol for feeding and care of diet-induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet^® 5k52) . At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to induce obesity (Research Diets, Inc. D12492i, 60 kcal% fat) . Mice have ad libitum access to food and water. Upon receipt of the animals from Jax labs, animals were kept under identical housing and feeding conditions to those at Jax labs ie. mice continued to receive the high fat diet listed above. For all substances known to be orally available in mammals, mice were treated in drinking water at 5x and 250x the recommended human therapeutic dose. For other compounds dosing was based on pub^¬ lished pharmacokinetics in mice or, where unavailable, based on the lowest functional dose in flies (ie. the lx and 50x the low^¬ est functional dose in flies) . Compounds known to be orally un^¬ available in mammals were administered once daily by manual in^¬ jection i.p. in a cellulose injection vehicle at doses determined as above. Body weight as well as food and water intake were monitored over the two week treatment period, and where mean body weight reductions relative to control animals were significant by t-test (p<0.05) and exceeded 2g (~ 5% of body weight) body fat composition was assessed by weighing total body weight, as well as peri-gonadal and subcutaneous fat pad weight at sacrifice. Compounds where changes in body weight correlate directly with changes in body fat composition were considered positive therapeutic candidates for treating mammalian obesity.

Example 3.1. Administration of Vandetanib

Vandetanib also known as ZD6474 is a tyrosine kinase inhibitor that functions as an antagonist of the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR) .

Vandetanib powder was obtained from Selleck Chemicals (S1046). Male C57B16/J DIO mice of 30 weeks of age were weight matched and housed in groups of 2 mice per cage and kept on 12-h light- dark cycle. Food and water were given ad libitum. 8 compound ad^¬ ministered mice (experimental) and 7 vehicle administered mice (control) were included in the experiment.

Mice were administered a daily dose of Vandetanib by oral ga- vage . Vandetanib was delivered in a vehicle consisting of 1% tween in PBS. Control mice were administered vehicle alone, daily, by oral gavage .

The dose of Vandetanib chosen for this study was 40mg/kg/d. This has been determined to be an effective dose for the inhibition of the target VEGFR in various mouse cancer models. In Choi et al 2008, Vandetanib was administered at a dose of 50 mg/kg/d by oral gavage in a vehicle of 1% tween 80 with PBS for 4 weeks in an orthopic nude mouse model of human Adenoid Cycstic Carcinoma. During the treatment period vandetanib was well tolerated by the mice and no adverse side effects or loss in body weight was ob^¬ served (Choi et al 2008) . This dose was effective to signifi^¬ cantly reduce tumour volume compared to vehicle administered controls (Choi et al 2008) . Treatment at a dose of 50mg/kg for 21 days in a renal cell carcinoma mouse model was well tolerated with no drug related changes in weight or behaviour observed (Drevs et al . , 2004) . This dose was also effective to reduce primary tumour volume (Drevs et al . , 2004) . Dosing in mice with Vandetanib in preclinical studies range from 12.5 to 150

mg/kg/day (Wedge et al . , 2002; Ciardiello et al . , 2003; Taguchi et al . , 2004; Damiano et al . , 2005). Generally a dose above 25mg/kg/day leads to an inhibition of tumour growth or induction of tumour regression whereas doses at or below this level tend to lead to a slowing of tumour growth (Wedge et al . , 2002;

Gustafson et al . , 2006) . Vandetanib has been administered to mice up to a dose of lOOmg/kg in mice for 35 days with no obvi^¬ ous effect on clinical condition (Wedge et al . , 2002) .

The DIO mice were weighed on the same day prior to the first compound administration (day 1) . The mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Vandetanib was well tolerated during the course of the study and no adverse side effects were observed. We observed an increased loss of weight in the compound adminis^¬ tered mice compared to the vehicle administered controls (Fig 1) . By day 13 we observed a statistically significant weight loss in the vandetanib administered mice compared to controls which was maintained for the duration of the experiment (p < 0.05; unpaired student t test).

On day 7 an Insulin tolerance test was performed (Fig 10) Al^¬ though the insulin response was similar in both experimental and control groups, we did observe a significant reduction in fast^¬ ing glucose levels in the experimental mice compared to the con^¬ trols (p < 0.05).

On day 35 an oral glucose tolerance test was performed (Fig 11) . We observed a reduction in the level of glucose levels at the 15, 45 and 60 minute time point after glucose administration in^¬ dicating that the vandetanib administered mice show an improved insulin response compared to controls (p < 0.05) .

On day 38 of compound administration the mice were sacrificed. The perigonadal fat pads were isolated and weighed. These values were expressed as a proportion of the body length of the mouse (Fig 12) . We observed a reduction of fat pad weight in the vandetanib administered group indicating the loss of weight in these mice is due to loss of fat pad mass (p < 0.05; unpaired student t test) .

Taken together these data indicate that Vandetanib leads to an almost 10% reduction of body weight that stabilized over the course of the experiment. The reduction in blood glucose levels and improvement of glucose handling are consistent with the ob^¬ served reduction in adiposity.

Example 3.2. Administration of Dasatinib

Dasatinib is a multiple BCR/abl Src family tyrosine kinase in^¬ hibitor. It is approved for use in the treatment of chronic mye^¬ logenous leukaemia.

Dasatinib was obtained as a powder from Selleck chemicals.

C57B16/J DIO mice of 19 weeks of age and weighing more than 33g were weight matched and housed in groups of 4 mice per cage and kept on 12-h light-dark cycle. Food and water were given ad li^¬ bitum. 5 dasatinib administered mice (experimental) and 4 vehi^¬ cle administered mice (controls) were used in the experiment. Mice were administered a dose of 5mg/kg/day daily of Dasatinib intraperitoneally in a vehicle of 1:1 propylene glycol/water . Control animals were administered the vehicle alone.

1.25mg/kg/dose BID or 2.5mg/kg/dose QD are considered to be the minimum efficacious dose based on studies in severe combined im- munodeficient mice bearing s.c. K562 xenografts (Lee et al . , 2004). The preclinical efficacious dose of 2.5mg/kg/day is ap^¬ proximately equivalent to a clinical does of 25mg/day (Luo et al . , 2006) . A dosing regimen in mice of 5mg/kg, PO) closely mimics the pharmacokinetics of the approved human once-daily dose of lOOmg. Based on this we decided to administer a dose of

5mg/kg/day in obese mouse models.

The DIO mice were weighed on the same day prior to the first compound administration (day 1) . The mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Dasatinib was well tolerated during the course of the study and no adverse side effects were observed. We observed a significant weight loss in the dasatinib adminis^¬ tered mice compared to the vehicle administered controls (Fig 13) . On day 5 we observed a significant weight reduction in the dasatinib group and by day 28 these mice had lost an average of 20% of their starting weight. This represented a statistically significant loss compared to vehicle administered mice (p < 0.001; unpaired student t test).

On day 15 an oral Glucose tolerance test was performed. Although both groups exhibit a similar fasting glucose level (time 0) there is an improved insulin response 15, 30 and 45 minutes af^¬ ter glucose administration in the experimental group (Fig 14) . This indicates that dasatinib leads to an improvement in insulin response and glucose clearance in mice fed a high fat diet.

On day 29 an oral glucose tolerance test was performed. We com^¬ pared the glucose measurements to that of the fasting glucose levels at time 0 (taken as 100%) in each group to determine the relative changes in glucose clearance (Fig 15) . We observed an improved glucose clearance in the dasatinib administered mice (45 mins p < 0.05; 60 mins p < 0.01) . Taken together the im^¬ provements in insulin sensitivity and glucose handling are con^¬ sistent with the observed reduction in weight.

References :

All of the following publications are incorporated herein by reference .

Altarejos et al . (2008) Nature medicine 14, 1112-1117.

Ashrafi et al . (2003) Nature 421, 268-272.

Baker et al . (2007) Cell metabolism 6, 257-266.

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Claims

Claims :

1. The method of reducing weight and/or body fat in a subject comprising the administration of the therapeutic compound

Vandetanib .

2. Vandetinib for use in a therapeutic method of reducing weight and/or body fat in a subject comprising the administra^¬ tion of the therapeutic compound Vandetanib.

3. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from Dasatinib, Tanespimycin , S-17092, and Sorafenib.

4. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from Lintopride, Fenoprofen, Sulfaphenazole, Fluticasone, Rolip^¬ ram, Febuxostat and Verapamil.

5. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from a modulator of gene CG9438, or an ortholog thereof, in par^¬ ticular the human orthologue CYP3A4, the compounds being se^¬ lected from erlotinib, gefitinib and lapatinib.

6. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from a modulator of gene CG8222, or an ortholog thereof, in particular the human orthologue KDR, the compounds being selected from axitinib, pazopanib and semaxanib.

7. The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from a modulator of gene CG6919, or an ortholog thereof, in par^¬ ticular the human orthologue HTR4, the compounds being selected from cisapride, mosapride, piboserod, prucalopride, renzapride, tegaserod, tropisetron and zacopride.

8. The method or compound of any one of claims 1 to 7 compris^¬ ing administration of the compounds in combination with any one or more therapeutic compound of table 1, preferably one or more compounds as defined in any one of claims 1 to 7.

9. The method or compound of any one of claims 1 to 8, charace- treized in that the treatment is for a therapy of obesity in the subj ect .

10. The method or compound of claim 9, characterized in that the patient suffers from severe Obesity with a body-mass-index (BMI) of at least 35, preferably a BMI of at least 40.

11. The method or compound of any one of claims 1 to 10, charac^¬ terized in that the compound is administered in an effective therapeutic dose.

12. The method or compound of any one of claims 1 to 11, charac^¬ terized in that the compound is administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or in^¬ traperitoneal, transdermal, transmucosal or inhalational .

13. The method or compound of any one of claims 1 to 12, charac^¬ terized in that the subject is mammal, preferably a human.

14. The method or compound of any one of claims 1 to 13, charac^¬ terized in that the compound or antagonist is provided in a me^¬ dicament .

15. The method or compound of any one of claims 1 to 14, charac^¬ terized in that the compound or antagonist is provided together with a pharmaceutically acceptable carrier or buffer.

16. The method or compound of any one of claims 1 to 15, charac^¬ terized in that the compound is administered in a dosage of be^¬ tween 0.01 mg/kg and 1 g/kg.

17. The method or compound of any one of claims 1 to 16, charac^¬ terized in that the therapeutic compound as defined in any one of claims 1 to 7 is administered as the only therapeutic com^¬ pound active in a treatment of reducing weight and/or body fat or of obesity in a subject.

18. Use of a compound as defined in any one of claims 1 to 7, preferably further defined as in any one of claims 8 to 17, for the manufacture of a medicament for the therapeutic administra^¬ tion to reduce body weight and/or body fat or to treat or pre^¬ vent obesity in a subject.