WO2019002542A1 - Combinaison d'un inhibiteur de mps1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant - Google Patents

Combinaison d'un inhibiteur de mps1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant Download PDF

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Publication number
WO2019002542A1
WO2019002542A1 PCT/EP2018/067572 EP2018067572W WO2019002542A1 WO 2019002542 A1 WO2019002542 A1 WO 2019002542A1 EP 2018067572 W EP2018067572 W EP 2018067572W WO 2019002542 A1 WO2019002542 A1 WO 2019002542A1
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combination
cancer
taxane compound
inhibitor
treatment
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PCT/EP2018/067572
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English (en)
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Frédérique CANTERO
Zakia FELLOUSSI
Marie SCHOUMACHER
Hélène LELIEVRE
Michaël Frank BURBRIDGE
Riccardo Colombo
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Les Laboratoires Servier
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to a combination of a MPSl inhibitor and a taxane compound. More particularly, the invention relates to a combination of iV-(2,6-diethyl phenyl)-8-( ⁇ 4-[4- (dimethylamino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro-lH- pyrazolo[4,3-h]quinazoline-3-carboxamide or one of its salts with a pharmaceutically acceptable acid or base and a taxane compound.
  • the invention also relates to the use of said combination in the treatment of cancer, in particular breast, lung, ovarian, bladder and prostate cancers, more particularly breast cancers. Also provided are pharmaceutical formulations suitable for the administration of such combinations.
  • Antimitotic agents and antimicrotubule agents have been explored for cancer therapy because of their important effect in the cell division. Inhibition of the mitotic machinery results in a diverse array of outcomes, primarily leading to cell cycle arrest and cell death.
  • Antimicrotubule agents such as taxanes are currently being used in clinical setting. For example, paclitaxel and docetaxel have a similar spectrum of clinical activity including ovarian, lung, breast, bladder, and prostate cancers. Taxanes are anti-mitotic agents that bind to tubulin and inhibit microtubule depolymerization thereby disrupting the normal equilibrium involved in microtubule assembly and deconstruction and therefore impair microtubule functioning.
  • Microtubules are essential to cell division and cells exposed to taxanes can fail to divide. Cell cycle arrest after treatment with taxanes may eventually result in cell death due to unsuccessful mitosis.
  • the toxicities associated with paclitaxel and docetaxel include neutropenia as the major dose limiting toxicity, along with significant peripheral neuropathy.
  • dose reductions are frequent in heavily pretreated patients to mitigate the severity of these toxicities.
  • the development of resistance to taxanes also limits its use in the clinic.
  • MMSl Monopolar Spindle 1
  • TTK Serine/Threonine kinase
  • SAC spindle assembly checkpoint
  • MPSl is highly expressed in breast and due to its role in mitosis, it is expected that the MPSl inhibitor have optimal efficacy in tumors with a high proliferation index such as triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • the standard systemic treatment in metastatic setting remains chemotherapy, as anthracyclins, taxanes with or without platinum (in particular in BRCA mutated patients). Even if overall response rate (ORR) obtained with the standard treatment by chemotherapy is high, the duration of response is short and the median survival is around 13 months.
  • ORR overall response rate
  • the progression- free survival (PFS) in first metastatic line remains poor, about 5-6 months, (even less after 2 nd and 3 rd line).
  • MPSl inhibitors By accelerating mitosis, MPSl inhibitors have a different mode of action compared to other antimitotic agents such as taxanes and the combination may enhance antitumor activity and promotes cell death.
  • the present invention thus provides a novel combination of a MPSl inhibitor and more particularly the N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethylamino)piperidin- 1 -yl]-2-methoxy phenyl ⁇ amino)- 1 -methyl-4,5-dihydro- lH-pyrazolo[4,3-h]quinazoline-3-carboxamide or one of its salts and a taxane compound.
  • the results show that combining disruption of microtubule function and MPSl inhibition in vivo is efficacious and well tolerated at different doses in female nude rats bearing MDA-MB-231 xenografts a model of triple negative breast cancer.
  • the synergistic effect of inhibiting MPSl and disrupting microtubule function in vitro and in vivo at tolerated doses have been demonstrated.
  • the present invention relates to a combination comprising: (a) N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethylamino)piperidin- 1 -yl]-2-methoxy phenyl ⁇ amino)-l-methyl-4,5-dihydro-lH-pyrazolo[4,3-h]quinazoline-3-carboxamide of formula (I):
  • the taxane compound is selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, Opaxio® (paclitaxel poliglumex), larotaxel, taxoprexin, BMS- 184476, hongdoushan A, hongdoushan B, hongdoushan C, and others.
  • the invention provides a combination comprising:
  • the invention provides a combination comprising:
  • the invention provides a combination comprising:
  • the invention provides a combination as described herein, for use in the treatment of cancer.
  • the invention provides the use of a combination as described herein, in the manufacture of a medicament for the treatment of cancer.
  • the invention provides a medicament containing, separately or together,
  • the invention provides a method of treating cancer, comprising administering a jointly therapeutically effective amount of:
  • the MPSl inhibitor is N-(2,6-diethylphenyl)-8-( ⁇ 4-[4- (dimethylamino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro- 1H- pyrazolo[4,3-h]quinazoline-3-carboxamide of formula (I), or one of its addition salts with a pharmaceutically acceptable acid or base.
  • the MPS1 inhibitor is N-(2,6-diethylphenyl)-8-( ⁇ 4-[4- (dimethylamino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro- 1H- pyrazolo[4,3-h]quinazoline-3-carboxamide phosphate salt of formula (II).
  • the taxane compound is paclitaxel.
  • the taxane compound is docetaxel.
  • Figure 1 illustrates efficacy of paclitaxel and N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethyl amino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro- lH-pyrazolo[4,3- h]quinazoline-3-carboxamide phosphate salt (compound 1) alone and in combination in cell line MDA-MB-468, a model of TNBC (triple negative breast cancer).
  • Figure 2 illustrates efficacy of docetaxel and N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethyl amino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro- lH-pyrazolo[4,3- h]quinazoline-3-carboxamide phosphate salt (compound 1) alone and in combination in an in vivo mice model of patient-derived xenograft tumors from TNBC residual tumors.
  • Figure 3 illustrates efficacy of paclitaxel and N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethyl amino)piperidin- 1 -yl]-2-methoxyphenyl ⁇ amino)- 1 -methyl-4,5-dihydro- lH-pyrazolo[4,3- h]quinazoline-3-carboxamide phosphate salt (compound 1) alone and in combination in an in vivo mice model of TNBC orthotopic xenografts.
  • Embodiment El a combination comprising:
  • compositions comprising a combination according to any of El to E8, in combination with one or more pharmaceutically acceptable excipients.
  • E21 The use according to E20, wherein the cancer is triple negative breast cancer.
  • E24 A medicament according to E22 or E23 wherein the taxane compound is paclitaxel.
  • E25 A medicament according to E22 or E23 wherein the taxane compound is docetaxel.
  • a method of treating cancer comprising administering a jointly therapeutically effective amount of:
  • a method of treating cancer comprising administering a jointly therapeutically effective amount of:
  • E28 A method according to E26 or E27 wherein the taxane compound is paclitaxel.
  • E29 A method according to E26 or E27 wherein the taxane compound is docetaxel.
  • E32 A method according to E30 or E31 wherein the taxane compound is paclitaxel.
  • E33 A method according to E30 or E31 wherein the taxane compound is docetaxel.
  • 'Combination' refers to either a fixed dose combination in one unit dosage form (e.g., capsule, tablet, or sachet), non-fixed dose combination, or a kit of parts for the combined administration where a compound of the present invention and one or more combination partners (e.g. another drug as explained below, also referred to as 'therapeutic agent' or 'co- agent') may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a compound of the present invention and one or more combination partners e.g. another drug as explained below, also referred to as 'therapeutic agent' or 'co- agent'
  • 'co-administration' or 'combined administration' or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term 'fixed dose combination means that the active ingredients, e.g. a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed dose combination means that the active ingredients, e.g. a compound of the present invention and one or more combination partners, are both administered to a patient as separate entities either simultaneously or sequentially, with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include solid tumors including carcinoma, sarcoma, or blastoma. In particular 'cancer' refers to breast and lung cancer.
  • jointly therapeutically effective means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • 'Synergistically effective' or 'synergy' means that the therapeutic effect observed following administration of two or more agents is greater than the sum of the therapeutic effects observed following the administration of each single agent.
  • the term 'treat', 'treating' or 'treatment' of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • 'treat', 'treating' or 'treatment' refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • 'treat', 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • a subject is 'in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • a patient who is sensitized is a patient who is responsive to the treatment involving administration of a MPS1 inhibitor of formula (I) or formula (II) in combination with a taxane compound, as described herein, or who has not developed resistance to such treatment.
  • 'Medicament' means a pharmaceutical composition, or a combination of several pharmaceutical compositions, which contains one or more active ingredients in the presence of one or more excipients.
  • the proportion of active ingredients by weight is from 5 to 50 %.
  • the pharmaceutical compositions according to the invention there will be more especially used those which are suitable for administration by the oral, parenteral and especially intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more specifically tablets, dragees, sublingual tablets, hard gelatin capsules, glossettes, capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels etc.
  • compositions according to the invention comprise one or more pharmaceutically acceptable excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings etc.
  • ⁇ as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,
  • ⁇ as lubricants silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
  • binders magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
  • ⁇ as disintegrants agar, alginic acid and its sodium salt, effervescent mixtures.
  • the compounds of the combination may be administered simultaneously or sequentially.
  • the administration route is preferably the intravenous infusion or injection, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
  • the compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are in admixture.
  • the useful dosage regimen could vary according to the sex, age and weight of the patient, the administration route, the nature of the cancer and of any associated treatments and ranges from 1 mg to 1000 mg of MPS 1 inhibitor per week, more preferably from 20 mg/m 2 to 50 mg/m 2 (expressed as phosphate salt) per week on Day 1, Day 8 and Day 15 of a 28-days cycle.
  • the dose of the taxane compound will be 70 or 80 mg/m 2 , the same dose as that used when it is administered on its own.
  • a bulk solution containing compound 1 , mannitol and Tween 80 is prepared, then lyophilized to obtain vials containing each 35 mg of compound of Example 1, 300 mg of mannitol and 5 mg of Tween 80.
  • Lyophilisate is re-suspended in 10 ml of water for injection.
  • EXAMPLE 1 Efficacy of V- ,6-diethylphenyl)-8-g4-r4-(dimethylamino)piperidin-l- yll-2-methoxyphenyl ⁇ amino)-l-methyl-4,5-dihvdro-lH-pyrazolo[4,3-hl uinazoline-3- carboxamide phosphate salt (compound 1) in combination with paclitaxel in TNBC cell line MDA-MB-468
  • MDA-MB-468 TNBC cells were treated with compound 1 alone and in combination with paclitaxel for at least 7 days in colony forming assay.
  • MDA-MB-468 Breast cancer cell lines were seeded at 400 cells/well in clear 96-well cell culture microplates (Euroclone) and incubated 48 hours before the treatment. Cells were treated, like it was done for plates treated for 72 hours, with paclitaxel, alone and in combination with compound 1 in a 5 x 9 dose matrix, using the HPD300e digital dispenser (TECAN). The final amount of DMSO was normalized at 0.2%. After treatment, the plates were put in the incubator for 7 days or longer, until the colonies of growing cells were clearly visible. The growth medium was then removed and the cells were fixed with 3.7% paraformaldehyde.
  • FS Fractional Survival
  • CTR DMSO treated controls
  • the combination index is calculated as ratio between experimentally measured survival values (FS) and predicted combination values:
  • FUA and FUB are the individual Fraction Unaffected of the two agents (A and B, A being compound 1 and B being paclitaxel) (Borisy, A A. et al, Systematic discovery of multicomponent therapeutics., Proc. Natl. Acad. Sci. USA 100, 7977-7982, 2003).
  • Combination index (C.I.) ⁇ 0.3 indicate strong synergism; 0.3-0.8 synergism; 0.8-1.2 additive; 1.3-3 antagonism; >3 strong antagonism. If the measured cell viability for the combination of two drugs is lower than the cell viability for both of the drugs acting as single agents and the C.I. is > 1.2, the effect is considered sub-additive.
  • TNBC cell line MDA-MB-468 the combination of compound 1 with paclitaxel is synergistic and increases the efficacy of each single agent as shown on Figure 1.
  • EXAMPLE 2 Efficacy of V- ,6-diethylphenyl)-8-q4-r4-(dimethylamino)piperidin-l- yll-2-methoxyphenyl ⁇ amino)-l-methyl-4,5-dihvdro-lH-pyrazolo[4,3-hl uinazoline-3- carboxamide phosphate salt (compound 1) in combination with paclitaxel or docetaxel in TNBC subcutaneous xenograft models
  • compound 1 The ability of compound 1 to inhibit tumor growth in combination with docetaxel was evaluated in subcutaneous patient-derived xenograft tumors from TNBC residual tumors after neo-adjuvant therapy.
  • Residual PDX was established from patient that did not respond or partially responded to 4 3- week cycles of 5-Fluorouracil + epirubicin + cyclophosphamide (FEC) followed 3-week cycles of docetaxel.
  • Swiss nude mice received subcutaneous grafts of human breast cancer fragments originated from a previous passage. Fragments for this assay will originate from at least 4 mice bearing the previous tumor passage and sacrificed when the tumors reached 12 to 15 mm of diameter (approximately 1 cm 3 volume). The treatment started when xenografts reached a mean tumor volume of ⁇ 50-100 mm 3 .
  • RTV relative tumor volume
  • MDA-MB-231 human breast carcinoma cells were engineered to express luciferase. Briefly, a synthetic firefly luciferase gene, Luc2 (pGL4, Promega) was cloned into the pLenti6.3/V5- DEST vector (Invitrogen). The ViraPowerTM Lentiviral Expression System (Invitrogen) was utilized to produce pLenti6.3-Luc2 lentiviruses and to transduce MDA-MB-231 cells. Stably transduced cells, termed "MDA-MB-231LUC2" were selected with blasticidin (10 ⁇ g/ml) and emit 4000 photons/sec/cell in presence of D-luciferin.
  • MDA-MB-231LUC2 cells were maintained in culture in RPMI 1640 medium with GlutaMAX, supplemented with 10% FCS and 1% penicillin- streptomycin (Sigma). 10 6 cells were injected into the mammary fat pad of the female athymic nude mice. After 8 days mice were randomized into treatment groups (on the basis of luminescence measurements) and treatments started 9 days later.
  • Compound 1 dissolved in glucose solution containing 1% Polysorbate 80 was administrated intravenously weekly at 20 mg/kg (expressed in terms of free base) in combination with paclitaxel dissolved in Cremophor : ethyl alcohol 1 : 1 and saline solution administrated intravenously weekly at 15 mg/kg for 3 weeks.
  • mice were injected intraperitoneally with 150 mg/kg D- luciferin (Promega), followed by anesthetization in a 2-3% isoflurane atmosphere. After 10- 12 minutes of bio distribution time, mice were imaged using a charge coupled device (CCD camera, Xenogen IVIS Lumina System) to evaluate whole body bioluminescence. A grayscale image of the mice was captured, followed by overlay of a bioluminescence map representing the spatial distribution of photons detected in the cancer cells expressing luciferase. Signal intensity was quantified using a customized version of the IGOR Pro version 4.09A Software (WaveMetrics, Inc., Lake Oswego, OR) called Living Image version 3.00 (Xenogen).
  • IGOR Pro version 4.09A Software WiveMetrics, Inc., Lake Oswego, OR
  • Photon emission was measured as radiance and expressed as photon/second/cmVsteradian.
  • the intensity of bioluminescence was color coded for imaging purposes.
  • the effect of the treatments was expressed as percentage of radiance inhibition respect to control group values.
  • Antitumor efficacy was also evaluated in terms of survival increase respect to control. T/C % value is calculated on the basis of the median survival time (MST) as:
  • the combination generated a marked antitumor response as revealed by the disappearance of tumor-derived bio luminescent signals at day 39 with a radiance inhibition of 99% compared with 63% for compound 1 alone.
  • Median estimated survival was greatly improved in combination group (higher than 151 days, 6/10 alive mice) compared with paclitaxel alone (87 days, p ⁇ 0.01) or compound 1 alone (62 days, p ⁇ 0.001) as shown on Figure 3.
  • phase I part will be conducted in metastatic breast cancer population with combination between N-(2,6-diethylphenyl)-8-( ⁇ 4-[4-(dimethylamino)piperidin- 1 -yl]-2-methoxy phenyl ⁇ amino)- 1 -methyl-4,5-dihydro- lH-pyrazolo[4,3-h]quinazoline-3-carboxamide, and more especially its phosphate salt (compound 1) and paclitaxel and will have as objectives the evaluation of the tolerance profile and the determination of the recommended doses of the combination for the continued development. Approximately 30 patients will be included in this part.
  • the patients will be treated by compound 1 with doses from 20 mg/m 2 to 50 mg/m 2 (expressed in terms of phosphate salt) per week in combination with 80 mg/m 2 or 70 mg/m 2 per week of paclitaxel in 28-day cycles.
  • phase II part will be initiated at the end of phase I part, with the objective of evaluating the activity of the combination between compound 1 and paclitaxel in comparison with paclitaxel alone in metastatic triple negative breast cancer population.
  • This phase II will include approximately 90 patients divided in two arms. The tumors will be evaluated every 2 months. Patients will be treated in 28-day cycle with the recommended dose of the combination (compound 1 and paclitaxel) and 80 mg/m 2 /week for the group with paclitaxel alone.
  • the treatment will be maintained until the disease progresses or patient's or physician's decision.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne une combinaison comprenant un inhibiteur de MPS1 de formule (I) ou l'un de ses sels d'addition avec un acide ou une base pharmaceutiquement acceptable, et un composé de taxane, ainsi que des compositions la comprenant et ses utilisations.
PCT/EP2018/067572 2017-06-30 2018-06-29 Combinaison d'un inhibiteur de mps1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant WO2019002542A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2023113477A1 (fr) * 2021-12-15 2023-06-22 Sillajen, Inc. Combinaisons pharmaceutiques destinées à être utilisées dans le traitement du cancer

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WO2009156315A1 (fr) * 2008-06-26 2009-12-30 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazolines
WO2014131739A2 (fr) * 2013-03-01 2014-09-04 Bayer Pharma Aktiengesellschaft Composés imidazopyridazines substitués

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WO2009156315A1 (fr) * 2008-06-26 2009-12-30 Nerviano Medical Sciences S.R.L. Pyrazolo-quinazolines
EP2303891A1 (fr) 2008-06-26 2011-04-06 Nerviano Medical Sciences S.r.l. Pyrazolo-quinazolines
WO2014131739A2 (fr) * 2013-03-01 2014-09-04 Bayer Pharma Aktiengesellschaft Composés imidazopyridazines substitués

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MARINA CALDARELLI ET AL: "Synthesis and SAR of new pyrazolo[4,3-]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 15, 31 May 2011 (2011-05-31), pages 4507 - 4511, XP028237583, ISSN: 0960-894X, [retrieved on 20110614], DOI: 10.1016/J.BMCL.2011.05.122 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023113477A1 (fr) * 2021-12-15 2023-06-22 Sillajen, Inc. Combinaisons pharmaceutiques destinées à être utilisées dans le traitement du cancer

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