WO1998055449A1 - Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires - Google Patents

Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires Download PDF

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Publication number
WO1998055449A1
WO1998055449A1 PCT/AU1998/000431 AU9800431W WO9855449A1 WO 1998055449 A1 WO1998055449 A1 WO 1998055449A1 AU 9800431 W AU9800431 W AU 9800431W WO 9855449 A1 WO9855449 A1 WO 9855449A1
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cells
compound
alkyl
abha
treatment
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PCT/AU1998/000431
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English (en)
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Peter Gordon Parsons
David Fairlie
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The University Of Queensland
The Queensland Institute Of Medical Research
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Priority to AU77516/98A priority Critical patent/AU7751698A/en
Priority to JP50113399A priority patent/JP2002513419A/ja
Priority to EP98925331A priority patent/EP0988280A1/fr
Publication of WO1998055449A1 publication Critical patent/WO1998055449A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to compounds which have anti-tumour and anti-parasite activity.
  • the compounds are selectively cytotoxic against tumour cells without killing normal cell types, and can be used either alone or in combination with other anti-cancer agents.
  • the invention relates to nitrogen-containing compounds, structurally related compounds, and derivatives thereof, which are selectively cytotoxic against tumour cells.
  • the compounds of the invention characteristically inhibit deacetylation of histones and modify gene expression.
  • the invention also provides pharmaceutical and/or veterinary compositions, and methods of treatment of cancer, of hyperplastic or dysplastic conditions such as psoriasis, leukoplakia, and solar keratosi ⁇ , and of parasite infections, utilising the compounds of the invention.
  • the invention provides methods for identifying particularly active compounds and for identifying patients likely to benefit from treatment with compounds of the invention.
  • Cancer is one of the major causes of morbidity and mortality in modern society. Chemotherapy against cancer traditionally involves the use of cytotoxic agents such as anti-metabolites or DNA-targeting drugs that indiscriminately kill normal cells as well as tumour cells. These agents therefore cause serious side effects that are usually dose-limiting. Most such drugs are also ineffective or poorly effective against solid tumours. Thus new antitumour agents based on alternative mechanisms of action are needed to overcome these problems.
  • One alternative method which may enable more selective targeting of tumour cells is conversion of cancerous cells to a non-proliferating phenotype through changes in gene expression. Studies of such reversion of oncogenically transformed cells to morphologically non- proliferating cells can provide valuable clues to aspects of the cell cycle which are still not fully understood.
  • a number of compounds known to differentiate tumour cells eg.
  • butyrate (1), retinoic acid (2), and N,N'- hexamethylene-bis-acetamide (HMBA; 3) (Marks et al , 1989) have undergone clinical trials, but all have suffered from problems of low potency, lack of selectivity, reversible differentiation or resistance.
  • HMBA has been reported to induce differentiation in vi tro in many types of neoplastic (Young et al , 1988) and epithelial cell lines (Andreef et al , 1988) and embryonic cells (Egorin et al 1987). It has induced remissions in myelodysplastic syndrome and acute myeloblastic leukemia (Breslow et al , 1991) , but suffers in vivo from rapid degradation through deacetylation, and causes side effects such as thrombocytopaenia, neurotoxicity and acidosis (Marks et al , 1994) .
  • HMBA In murine erythroleukaemic cells, HMBA induces arrest in GI , promotes translocation of protein kinase C (PKC) from the cytosol to the membrane, decreases c-myb, c-myc and p53 protein levels, and increases c-fos mRNA.
  • PKC protein kinase C
  • a transient increase in hypophosphorylated retinoblastoma protein pRB was found 12 hr after treatment, followed by enhanced production of the hyperphosphorylated form ppRB during the next 2-3 days (Richon et al , 1992; Kiyokawa et al , 1994) .
  • Azelaic bishydroxamic acid (ABHA; 4) and some of its analogues were up to 100-fold more active than HMBA.
  • a preferred compound is ABHA (4) .
  • the compounds are stated to induce terminal differentiation of neoplastic cells and thereby to inhibit proliferation of these cells, but the activity requires prolonged contact of the compounds with the cells, preferably for at least 4 to 5 days .
  • Activity against murine erythroleukae ia cells and acute promyelocytic leukaemia cells was observed in the range 1 to 2,500 ⁇ M (80 compounds tested, with one being inactive) and the range 1 to 20 ⁇ M (16 compounds tested) respectively.
  • any of the compounds, including ABHA exerts selective toxicity against tumour cells, as distinct from normal cells. Nor is there any suggestion in the prior art that these compounds might have any activity against parasites .
  • TSA histone deacetylase inhibitor trichostatin
  • SV40-transformed cells are not tumour cells and generally do not form tumours in animals
  • TSA although selectively toxic to some human tumour cells in culture, is metabolised by cultured cells, and is inactive against human tumour cells in vivo .
  • HC-toxin a cyclic peptide proposed for the treatment of malaria (Darkin-Rattray et al , 1996), has properties similar to TSA, ie. it is tumour-selective in vi tro, but is inactivated by cultured cells and lacks antitumour activity in vivo, even when used at high doses.
  • Melanocytes and melanoma cells express a range of differentiation markers related to pigment synthesis, including tyrosinase, HMB-45, melanin and the tyrosinase- related protein-1 (TRP-1) (Takahashi and Parsons, 1990; Sturm et al , 1994) .
  • TRP-1 tyrosinase-related protein-1
  • ABHA has poor activity as a differentiating agent with respect to pigmentation, which is the major differentiation pathway in melanocytic cells, and indeed that ABHA in some respects may act as a de-differentiating agent.
  • ABHA was unusual, in being cytotoxic for transformed cells but not for normal cells, while activating the transcription of certain genes involved in signal transduction.
  • This invention relates to compounds having the ability to selectively prevent the growth of a variety of human tumour cell types, without affecting the growth of normal human cells.
  • the invention relates to nitrogen-containing compounds, structurally-related compounds, and derivatives thereof.
  • the compounds are hydroxamate or bishydroxamate compounds or derivatives thereof.
  • the compounds are cyclic peptides.
  • the compounds of the invention are selectively cytotoxic to human tumour cells both in cell culture, and in animal models in vivo .
  • tumour cells are to be understood to mean that proliferation of tumour cells in vi tro is irreversibly inhibited, but normal cells are still able to proliferate, when exposed to a compound of the invention under comparable conditions.
  • the invention provides a method of treatment of cancer, comprising the step of administration of an effective amount of a compound of the invention to a mammal in need of such treatment, said compound having selective cytotoxicity for neoplastic cells compared to normal cells, and having minimal or absent ability to induce differentiation in neoplastic cells.
  • the compound is selected from the group consisting of hydroxamates , bishydroxamates , or derivatives thereof, and cyclic peptides.
  • the compound has the ability to inhibit deacetylation of histones .
  • the compound also enhances the Sphl- containing promoter and/or the zinc-induced activity of the metallothionein la promoter.
  • the compound is selectively toxic to cells that express low levels of full length RbAp48.
  • the compound is not ABHA.
  • compounds of the invention either have no effect on, or down-regulate, expression of classical markers for differentiation in human melanoma cells.
  • TRPl is down-regulated, while HMB-45and tyrosinase are not significantly affected.
  • the method of the invention may be used in conjunction with one or more other anti-cancer therapies, such as chemotherapy or radiotherapy.
  • the method of the invention may be used in conjunction with one or more antiproliferative agents, such as cytosine arabinoside, 5-fluorouracil, , methotrexate, chlorodeoxyadenosine, etoposide, taxol (paclitaxel) , and the like.
  • the other treatment may be administered either concurrently, prophylactically or following the compound of the invention.
  • the compounds of the invention are useful for treatment of all types of cancer, including leukaemias and lymphomas, it is considered that these compounds will be particularly advantageous in the treatment of solid tumours, such as melanoma and other skin cancers, ovarian cancer, cervical cancer, breast cancer, prostate cancer, endometrial cancer, lung cancer, gastric cancer, colon cancer and the like.
  • solid tumours such as melanoma and other skin cancers, ovarian cancer, cervical cancer, breast cancer, prostate cancer, endometrial cancer, lung cancer, gastric cancer, colon cancer and the like.
  • the method of the invention is particularly contemplated for treatment of human cancer, it is also applicable to veterinary treatment.
  • the mammal may be a human, or may be a domestic, companion or zoo mammal, including but not limited to cattle, horses, sheep, goats, deer, cats, dogs, and large felids.
  • the compound is selectively toxic for at least one type of tumour cell, ie. the compound exerts a toxic or antiproliferative effect against the tumour cell but not against normal cells .
  • All the compounds of the invention have one or more of the following activities: a) inhibition of growth in cell culture of at least one of the following human tumour cell lines: melanoma MM418cl, cervical HeLa, melanoma A2058, ovarian JAM, and lymphoma Mutu; b) inhibition of growth in cell culture of transformed keratinocytes (HaCat) and melanocytes (Mel-SV) ; c) inhibition of growth in vivo of human tumour cells ( eg.
  • melanoma MM96L in xenografted nude mice; d) inhibition of histone deacetylase, as measured by extent of hyperacetylation of histones; e) induction of differences in protein expression by human tumour cells compared to normal human cells; f) selective killing of tumour cells in (a) without killing normal cells; g) blocking of cell cycle progression of some sensitive tumour cells in the Gl/S phase; h) induction of apoptosis in tumour cells; and i) inhibition of DNA synthesis in normal but not in tumour cells .
  • the compounds do not: a) kill normal human cells, eg. melanocytes, neonatal foreskin fibroblasts (NFF) , or peripheral blood lymphocytes, at dosages effective for killing human tumour cells; b) significantly inhibit metalloproteinases known to be important for tissue maintenance and protein regulation, at a Ki equal to or less than 1 ⁇ M; c) show overt signs of toxicity in animal models ; d) block the cell cycle of some drug-sensitive tumour cells at G 2 /M phase.
  • normal human cells eg. melanocytes, neonatal foreskin fibroblasts (NFF) , or peripheral blood lymphocytes
  • c) show overt signs of toxicity in animal models
  • d) block the cell cycle of some drug-sensitive tumour cells at G 2 /M phase.
  • the compounds of the invention are effective in killing transformed keratinocytes. Therefore in a second aspect, the invention provides a method of treatment of a hyperplastic or dysplastic condition, comprising the step of administering an effective amount of a compound as defined above or of ABHA to a subject in need of such treatment.
  • the condition is a keratinous hyperplasia, such as psoriasis, leukoplakia or solar keratosis .
  • the invention provides a hydroxamate or hydroxamic acid compound of general formula la or lb or Ic,
  • R 1 and R 2 are the same or different, and each is independently selected from the group consisting of H; OH; NH 2 ; NHOH; substituted or unsubstituted, branched or unbranched alkyl , alkenyl, alkylamino, alkyloxy or arylalkyloxy; substituted or unsubstituted aryl, aryloxy or pyridino; substituted or unsubstituted arylamino, piperidino, cycloalkyl, cycloalkylamino, pyridineamino, 9-purine-6-amine, and thiazoleamino; and the linker is a group having a backbone of 5 to 9 atoms, which may comprise 1, 2 or 3 amino acids, or a pharmaceutically-acceptable salt, ester or derivative thereof.
  • the two X 1 groups are independently selected from the listed groups.
  • the compound is of formula II :
  • R 3 is as defined above for R 1 and R 2 .
  • R 4 and R 5 are the same or different, and is each independently selected from H, alkyl, aryl or a side-chain of a common or uncommon amino acid.
  • a "common" amino acid is a -amino acid selected from the group consisting of glycine, leucine, isoleucine, valine, alanine, phenylalanine, tyrosine, tryptophan, aspartate, asparagine, glutamate, glutamine, cysteine, methionine, arginine, lysine, proline, serine, threonine and histidine.
  • an "uncommon" amino acid includes, but is not restricted to, D-amino acids, homo-amino acids, N-alkyl amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan) , ortho-, meta- or para-aminobenzoic acid, ornithine, citrulline, norleucine, ⁇ -glutamic acid, aminobutyric acid and ⁇ , ⁇ -disubstituted amino acids.
  • the linker comprises two amino acids, and the compound is of formula Ilia or Illb:
  • the linker comprises one amino acid, and the compound is of general formula IVa,
  • -CH CH-C 6 H 4 -CO; or -CH (alkyl ) -CH (alkyl ) CO .
  • R 3 , R 4 and R 5 are as defined above.
  • the linker comprises 1, 2 or 3 double bonds, and the compound is of the formula Va,
  • Vb, Vc, Vd Ve, Vf or Vg are Vb, Vc, Vd Ve, Vf or Vg,
  • each of R 1 and R 2 is independently H, alkyl or aryl,
  • the polar group X" forms part of a cyclic tetrapeptide of formula VI,
  • each of R 3 , R 4 and R 5 are the same or different, and are as defined above, or may be thioproline, hydroxyproline, pipecolic acid, or decahydroisoquinoline;
  • X 1 and Y are as defined above, or Y may be (CH 2 ) 5 COMe, (CH 2 ) 4 COMe, (CH 2 ) 5 C0-alkyl , (CH 2 ) 5 CO-aryl, or (CH 2 ) 5 CO-NR 3 R 6 , wherein R 3 and R 6 are the same or different, and are as defined above.
  • each of R 3 and R 6 is selected from the group consisting of H, alkyl, aryl, (CH 2 ) 5 CHO,
  • amino acids is optionally N-alkylated with an aliphatic alkyl group.
  • the stereochemical configuration at the position marked by * may be R or S (L or D) .
  • the polar group X 1 forms part of a cyclic pentapeptide, and the compound is of formula VIII,
  • compounds of the invention are cyclic molecules, such as quinolines, isoquinolines, tetrahydroquinolines , or decahydroquinolines ; or a compound selected from the group consisting of
  • n 0 ,1,2 and
  • Z is 0, S, NH, N-alkyl; NO; SO; CO;
  • X 2 is 0, OH, aldehyde, ketone, CF 3 ; N0 2 ; NO; SH; S; NH; NH 2 ; C0 2 H; CONH 2 ; C0 2 (alkyl); CONH (alkyl); or other polar group;
  • R 7 is one or more substituents such as H; OH; OMe; N0 2 ; Cl; Br; F; (Me) 2 N; CN; NH 2 : NH(alkyl); N (alkyl) 2 ; S0 3 H; S0 2 NH 2 ; alkyl CF 3 ; 0(alkyl); SH; S (alkyl) etc, and in which each bond depicted as an alkene bond may alternatively be a single bond, and each single bond marked with a circle may alternatively be a double bond.
  • substituents such as H; OH; OMe; N0 2 ; Cl; Br; F; (Me) 2 N; CN; NH 2 : NH(alkyl); N (alkyl) 2 ; S0 3 H; S0 2 NH 2 ; alkyl CF 3 ; 0(alkyl); SH; S (alkyl) etc, and in which each bond depicted as an alkene bond may alternatively
  • the invention provides a composition
  • a composition comprising a compound of the invention, general formulae or a pharmacologically acceptable salt, ester or derivative thereof, together with a pharmaceutically or veterinarily acceptable carrier.
  • the invention provides a method of treatment of a protozoal parasite infection, comprising the step of administering an effective dose of one or more compounds of the invention, or of ABHA or a related compound, to a subject in need of such treatment .
  • this aspect of the invention is applicable to the treatment of infection with a variety of protozoal parasites, including but not limited to protozoa of the genera Giardia , Crypto sporidium, Trichomonas , Histomonas, Plasmodium, Toxoplasma, Trypanosoma, Babesia , Balantidium, Naegleria , Entamoeba , Eimeria, Schistomaniasis , other intestinal parasites, and the like. Many of these parasites present major public health or veterinary problems, particularly in developing countries, and currently-available therapies are unsatisfactory.
  • the parasite is Giardia , particularly Giardia duodenalis, Plasmodium, particularly Plasmodium falciparum, or Trichomonas , preferably Trichomonas vaginalis .
  • the compound is AAHA, MW2796, MW2996, as herein defined, or ABHA. More preferably the compound is MW2796.
  • the invention provides a method of identification of cancers which are particularly amenable to treatment by the method of the invention, comprising the step of detecting abnormal levels or absence of full length RbAp48 in a sample of the cancer.
  • this may be achieved by subjecting a histological section of the tumour, obtained via biopsy or at the time of surgical excision of the tumour, to immunohistochemical analysis with an antibody directed to RbAp48.
  • the antibody may be labelled with any suitable detectable marker, and fluorescent or radioactive markers are preferred. Fluorescent markers are particularly preferred.
  • the compounds of the invention may be administered by any suitable route, including but not limited to parenteral injection, for example intravenous, subcutaneous, intramuscular and intratumoural injection, oral administration, transdermal and topical administration. In general oral, transdermal or topical administration is preferred. It is expected on the basis of the general chemical properties of hydroxamates and related compounds that at least some compounds useful for the purposes of the invention will be orally bioavailable, and we have demonstrated that this is the case. Structural modifications whereby oral bioavailability can be improved are known in the art; see for example Beckett et al , 1996.
  • a suitable dose range will be 0.1 to 100 mg/kg body weight, administered in single or divided doses. For example, three separate doses per day may be used. Alternatively continuous infusion via a pump may be used.
  • suitable carriers and formulation agents is known in the art, and reference may be made for example to Remington's Pharmaceutical Sciences, 19 th Edition, Mack Publishing Company, Easton, Pennsylvania.
  • the formulation will depend on the dose and route to be used, and is a matter of routine trial and error experimentatio .
  • the invention provides a method of enhancing the selectivity of treatment of a cancer or of a protozoal parasite infection with a compound of the invention, comprising the step of administering a nucleic acid sequence complementary to a nucleic acid sequence encoding RbAp48 or to an Sphl-containing sequence to the subject to be treated.
  • the complementary sequence is targeted to tumour cells or to protozoal parasites .
  • the invention provides a method of increasing the proportion of tumour cells recognised by the immune system, comprising the step of administering a compound of the invention to a subject suffering from the tumour, thereby to increase the proportion of tumour cells expressing MHC Class I molecules.
  • This relates to use of compounds of the invention, or of ABHA and related compounds, to modulate immune responses of patients with cancer or any other conditions where enhancement of the immune system or of immunoregulatory molecules is required.
  • the invention insofar as it pertains to compounds per se and to pharmaceutical compositions per se for the treatment of cancer, does not include azelaic bishydroxamic acid or compounds disclosed in WO 95/31977 or WO 93/07148.
  • Figure 1A shows the enhanced dendritic morphology induced in melanoma cells (A,B) or HeLa cells (E,F) but not in normal melanocytes (C,D), or neonatal foreskin fibroblast cells (NFF, G,H).
  • Inhibitor azelaic bishydroxamic acid (ABHA) , 100 ⁇ M.
  • Figure IB shows apoptosis (programmed cell death) in cells treated with 100 ⁇ g/ml ABHA for 24 hr, fixed in methanol and stained with Hoechst 33248. Apoptotic cells have fragmented nuclei. Left panels, untreated cells.
  • A,B MM96L cells.
  • C,D HeLa.
  • E,F MM229 cells.
  • G,H human neonatal foreskin fibroblasts (NFF) .
  • Figure 2 shows flow cytometry profiles illustrating the ability of compounds of the invention to block cell proliferation.
  • Tumour cells MM96L and HeLa
  • normal cells NFF, D29
  • TSA trichostatin A
  • Mk-4 same as azelaic-l-hydroxamate-9- anilide (AAHA)
  • HU hydroxyurea .
  • Figure 3 illustrates the selective inhibition of tumour cell growth by ABHA.
  • Panel A shows the response for melanocytes
  • Figure 4 shows the loss of hyperphosphorylated retinoblastoma protein (RB) in cells treated with ABHA (13 ⁇ g/mL) or hexamethylene bisacetamide (HMBA: 1,000 ⁇ g/mL) for either 12 hr or three days.
  • ppRB represents hyperphosphorylated RB (115 kDa)
  • pRB represents hypophosphorylated RB (105 kDa) .
  • FIG. 5B shows the induction of transcription in HeLa cells after 24 hr treatment with ABHA or AAHA, using a variety of promoter constructs driving the luciferase gene and measured as luciferase activity by luminescence.
  • the SphI sequence is identified as the sequence essential for full activation.
  • Oct octamer sequence derived from the SV40 enhancer region, and inserted into the pGL2 reporter construct; SphI: the SphI sequence; SphII: the Sphll sequence; wt : wild type; dpm2 , dpm7 and dpm8 : similar sequences containing the mutations identified in bold type
  • Figure 5C shows that the SphI activity is induced by all histone deacetylation inhibitors tested, but only in cells expressing the tumour-suppressor gene, pl6.
  • Figures 6A, 6B and 6C show growth of xenografted
  • MM96L human melanomas in nude mice which had been treated with ABHA at 4 mg/day, AAHA at 5 mg/day, SBHA at 8 mg/day, TSA at 25 ⁇ g/day or HC-toxin at 25 ⁇ g/day.
  • • treated with ABHA, AAHA or SBHA;
  • ⁇ treated with TSA or HC-toxin;
  • Figure 7A shows the results of two-dimensional polyacrylamide gel electrophoresis comparing cell extracts of the melanoma cell line MM96L (a) with and (b) without treatment with 100 ⁇ g/ml ABHA.
  • Small black arrows indicate proteins that are lost due to drug treatment; small white arrows indicate proteins that are gained due to drug treatment .
  • Figure 7B shows two one-dimensional PAGE gels of proteins separated from control and treated cells .
  • Bold arrows show proteins that are specifically induced by ABHA (100 ⁇ g/ml for 24 hr) or by UBV (240 Joules/m 2 radiation for 24 hr) in sensitive cells.
  • the cells used were MM96L and A2058 melanoma cell lines, MEL/SV40 SV40-transformed melanocytes and NFF cells.
  • * shows the location of BSA derived from the FCS, the presence of which obscures this region of the gel.
  • M molecular weight markers
  • C control .
  • Figure 7C shows a western blot of MM96L cells, reacted with 0V9D1 antibody to Ku86.
  • the level of this protein (at 86 kDa) is upregulated in the cytosol (C) and depleted in the nucleus (N) by ABHA treatment (100 ⁇ g/ml for 24 hr) .
  • Figure 8 shows a pharmacophore model in which the structures of active (grey) and inactive (white) compounds are overlaid.
  • Figure 9A shows acetylation of histone H4 during 24 hr treatment of MM96L cells with 100 ⁇ g/ml ABHA (lane C: control, lane A: ABHA treated) or treatment of HeLa cells with 5 mM sodium butyrate (lane C: control; lane B:, treated); H: histone mixture. Bands were visualised by protein staining of polyacrylamide gel separated acid- soluble material.
  • Figure 9C shows a laser densitometry trace of the time course of histone H4 acetylation during treatment with ABHA, in MM96L cells (top panels) and NFF (lower panels) .
  • Figure 9D shows the rate of loss of acetylated histone H4 after removal of ABHA from the culture medium.
  • Cells had been treated previously with 10 ⁇ g/ml ABHA for 24 hr.
  • Figure 10A shows the levels and relative sizes of proteins in cell lysates reactive with RbAp48 antibody, as revealed by western blotting.
  • Sensitive cell lines eg. MM96L, HeLa
  • Figure 10B shows that hybrids between sensitive (HeLa) and resistant (NFF or A2058) cells tend to express a pattern of RbAp48 proteins that resembles that of the sensitive parent line; ie.: there is less full length protein (48kDa) than would have been expected from the parent resistant line.
  • A/H mp2 , A/H B5 are A2058/HeLa hybrids.
  • N/H mp are NFF/HeLa hybrids.
  • Figures 11A and B show the instability of 100 ng/ml TSA (A) and HC-toxin (B) in the presence of cultured cells, compared with ABHA.
  • the dose response for inactivati ' on of HC-toxin (panel B) was conducted using 24, 48 and 72 hr exposures to MM96L cells and compared with incubation in culture medium alone for 72 hr .
  • Drugs were incubated in microtitre plates with 50,000 MM96L cells per well, and at various times the medium was transferred to another plate containing 5000 MM96L cells for a 24 hr treatment, followed by a further 5 day incubation for determination of cell survival.
  • FCS foetal calf serum
  • NFF were human neonatal foreskin fibroblasts. Normal human melanocytes from foreskins were cultured in 100 ⁇ g/mL, 12-O-tetradecanoyl- phorbol 13 -acetate and 6 ⁇ g/ml cholera toxin.
  • the mel-SV line of immortalised human melanocytes obtained after infection of melanocytes with an SV40-adenovirus 5 hybrid virus, was kindly provided by Prof. P. Gallimore (Birmingham, U.K.) Cultures were grown at 37°C in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 5% foetal calf serum (FCS) as previously described. Cell survival was determined by performing haemocytometer counts of the increase in number of 25,000 cells seeded in 24-well plates (16 mm diameter wells) and treated v/ith drug for 24 hr, washed twice and incubated for 3 doubling times (6 days for NFF, melanocytes and MM418; 3 days for the other cell lines) .
  • cell numbers are determined with the MTS/PMS method or by assessing 3 H-thymidine incorporation, which gives similar results (Parsons et al , 1997).
  • Assays for galactosidase action using chlorophenol red galactoside (CPRG) substrate may be performed in microtitre plates and read using a ELISA reader (Wong et al , 1994) .
  • treated cells were compared with controls on the basis of equal cell number or protein content, the latter determined by addition of bichinchoninic acid reagent (Pierce Chemical Co, USA) to triplicates in a microtitre plate and determining the absorbance increase at 570nm.
  • Bovine serum albumin was used as the standard.
  • Tyrosinase (dopa oxidase) activity was measured by the oxidation of L-dopa as described (Takahashi and Parsons, 1990) .
  • Immunoblotting was conducted using B8G3 mouse monoclonal antibody supernatant against TRP-1 or HMB- 45 mouse antibody (diluted 1 in 250) , followed by alkaline phosphatase-conjugated anti-mouse antibody, and was quantitated by a Molecular Dynamics laser densitometer with ImageQuant software.
  • LuciferaseTransfectants Clones of MM96L and HeLa cells stably transfected with reporter plasmids were used to determine the effect of ABHA on promoter activities. Construction of the TRP-1 promoter has been described (Sturm et al , 1994) . The SV40 promoter/enhancer construct was obtained from Promega . For construction of a reporter containing a p53 response element, a duplex oligonucleotide containing a strong palindromic p53 recognition site (Funk et al , 1992) was cloned as a blunt-ended fragment
  • Histone Hyperacetylation was determined by acid extraction of nuclear proteins, followed by PAGE or Triton/urea gels, and staining of gels with Coomassie blue stain. Alternatively, hyperacetylation may be determined indirectly by accessibility of DNA to Hoechst 33258, using flow cytometry, and directly by PAGE. Levels of histone deacetylase and acetyi transferase are measured by Western blotting, or by RT-PCR from the published sequences. cDNA is used for constructing expression vectors, as carried out for Brn-2 antisense sequences (Thompson et al , 1995).
  • Xenografts of melanoma MM96L, HeLa and the ovarian cancer cell line JAM were grown in nude mice (6 per group, 2 sites per mouse on the flanks) as described previously (Parsons et al , 1991) .
  • drug treatments in saline were given i.p. once daily to 3 mice at a concentration just below any toxic level found, then at a lower, more efficacious dose to all 6 mice in each group.
  • no general toxicity has been found for ABHA.
  • the size of tumours was measured weekly, and animals euthanised when the tumour reached 1 cm diameter. If any tumours developed in treated mice, tumour cells were isolated back into culture to determine if resistance had developed.
  • IPG immobilised pH gradient
  • Focussing normally requires 250,000 volt/hours.
  • the IPG gels were then separated in polyacrylamide gels (4%-15%) and silver stained.
  • the protein extract is first mixed with 10 mg/mL of radiolabelled differentiating agent and viewed by autoradiography at the end of the experiment. Specific proteins can be extracted directly from acrylamide gels or electroblotted onto PVDF membrane.
  • Protocols used in all studies are similar to those used in the Australian Proteome Analysis Facility (APAF) , Macquarie University.
  • a suitably functionalised differentiating agent is linked to the surface of a CM-5 chip through a series of glycine residues using standard solid phase peptide coupling.
  • Cell lysates are then fractioned to remove particulate matter and passed over the immobilised differentiating agent.
  • the immobilised material is then washed with buffered saline and desorbed (usually by changing pH or ionic strength) . Desorbed material can be collected and run on gels to identify which bands in the 2D-PAGE experiments are binding. Up to 30 ng of protein is collected from a single BiacoreTM experiment, although this depends on the strength of the interaction and number of receptors . It may be necessary to prepare an affinity column to obtain sufficient protein for analysis.
  • Tresyl Sepharose or similar Cell lysates (10° or more cells) prepared in 0.5% Triton X-100 are diluted into low salt buffer and after washing unbound material away Sepharose-bound proteins are eluted with batches of NaCl (to 2M) and finally by electroelution. Fractions are run on PAGE gels with silver detection of proteins. Relevant bands from a large scale preparation are transferred to PVDF membrane and the protein N-terminus sequenced by MSMS and tryptic digests.
  • LogP values are predicted using PALLAS pKalc and PrologP programs (Compudrug Chemistry Ltd, Hungary) , and measured using a HPLC elution rates and a standard calibration curve with control compounds of known LogP.
  • HeLa cells, human fibroblasts or any other desired test cells are seeded at 10 ⁇ cells per mL and grown in Dulbecco ' s Modified Eagles Medium (DMEM) supplemented with 10% foetal calf serum (FCS) at 37°C. After 20 hr, medium is removed, cells are washed twice with 5 mL of medium (without FCS) and test compound labelled with a suitable isotope is added to cells at varying concentrations (0.05 - 1 mM) in DMEM. Cells are grown for 20 hr more, washed twice with ice-cold DMEM, and counted in a liquid scintillation counter.
  • DMEM Dulbecco ' s Modified Eagles Medium
  • FCS foetal calf serum
  • the transformed kidney cell line 293 formed large aggregates of cells instead of flattened colonies. Cells ceased to proliferate after several days treatment, but there were no signs of overt toxicity until higher doses were used (100 ⁇ g/ml ABHA) . Apoptotic cells were detected, as shown in Figure IB, and tended to be more numerous in sensitive cell types (MM96L, HeLa) than in resistant cells (NFF, MM229). This is summarized in Table 1.
  • ABHA was 100-fold more potent for inhibiting growth than HMBA or azelaic acid. Treatment for 24 hr was about 10-fold less effective than for 6 days, but the former treatment time was further explored because of the limited exposure period anticipated in vivo . Compared on the basis of cell growth for 3 doubling times following a 24 hr treatment, ABHA was found to be highly selective against tumour cell lines compared with fibroblasts and melanocytes .
  • Table 2 summarises results obtained from a much larger number of cell types. These confirm the trend observed above, except for several melanoma cell lines (A2058, MM229) which showed some resistance to ABHA. It should also be noted that TSA was selective against a smaller range of cell lines than ABHA; AAHA, however, shows selectivity similar to ABHA but has slightly greater potency. Table 2 Toxicity of Histone Deacetylase Inhibitors in Human Cells
  • ABHA and AAHA are of relatively low potency, the key finding is the selectivity of these compounds in killing melanoma, ovarian and cervical tumou: cells, and a range of other tumour cell types without affecting growth of normal cells like melanocytes and fibroblasts. This is a novel result.
  • the basis for this in vi tro selectivity for tumour cells and the cellular target (s) are elaborated below.
  • Example 2 Expression of Pigmentation Markers and pRB
  • the results are summarised in Table 3.
  • ppRB hyperphosphorylated pRB
  • RNA and protein requirements associated with ABHA-induced differentiation were investigated in HeLa cells. 5 x 10 4 cells were treated in a microtitre plate with 10 and 100 ⁇ g/ml ABHA for 24 hr . 10 ⁇ g/ml cycloheximide or 2 mg/ml actinomycin D was added at 0 , 5, 10, 18 and 24 hr . The cells were then fixed with 5% acetic acid in ethanol, and stained with IFA. The dendritic cells in each well were counted, either manually or by image analysis on the inverted microscope, on the basis of cell shape . There was an 80% reduction in the number of dendritic cells formed in response to ABHA in the presence of either of the inhibitors . ABHA-induced differentiation therefore is dependent on both RNA and protein synthesis, suggesting that ABHA is not acting solely as an inhibitor of cellular functions, but also induces the transcription of genes involved in differentiation.
  • MM96L showed inhibition of p53-activation in a 24 hr treatment.
  • c-Fos promoter activity was strongly inhibited in HeLa but not in MM96L, following a 6 hr treatment with ABHA.
  • ABHA and AAHA was found in association with a motif which forms part of the SV40 and mammalian gene promoters.
  • a range of different promoter constructs showed that the SphI sequence (AAG CAT GC) was responsible for this activation, as illustrated in Figure 5B.
  • Activation occurred with all histone deacetylase inhibitors tested, but was only observed in cells that over-expressed the tumour suppressor gene, pl6, as shown in Figure 5C . This finding is relevant to identifying the range of mammalian genes that are activated by such drugs.
  • the A4/4 cell line is a derivative of 293 cells, which were shown in Table 2 to be sensitive to ABHA and AAHA.
  • A4/4 cells were transfected with a reporter plasmid that is silenced by DNA methylation.
  • Treatment with a demethylating agent (5-azacytidine; Biard et al , 1992) inhibits DNA remethylation of the daughter strand after cell division, allowing recovery of the reporter activity, detected as ⁇ -galactosidase.
  • Treatment of A4/4 cells for 40 hr gave substantial increases in reporter activity, as summarised in Table 5.
  • Xenografts of melanoma cell line MM96L were established in BALB/c nude (nu/nu) mice.
  • One group of mice was treated with compounds of the invention at a dose of 4 mg/day by intraperitoneal injection. Because of limited supplies of the compounds, the dose could only be administered at 5/7 days per week.
  • the growth of the melanoma was significantly inhibited by treatment with ABHA, AAHA and SBHA, compared to control, untreated mice.
  • the melanoma cell line MM96L is resistant to treatment by conventional antitumour agents, both in vi tro and in vivo . Indeed, as far as we are aware, these are the first compounds which have been demonstrated to inhibit the growth of this cell line.
  • TSA and HC-toxin were inactive, even though the doses used were 5-10 fold higher than the equivalent dose of ABHA.
  • hydroxamate compounds have been synthesised within our group, and by others (Lofas and Johnsson, 1990) .
  • the carbon chain length has been varied and replaced by rigid spacers, for example aromatic rings and cinnamyl groups as in 5.
  • Ri or R 2 is H, alkyl, etc.
  • R 3 is N0 2 , halogen, NH 2 , OH, etc .
  • Ri H ; OH ; 0CH 3 ; Cl ; Br ; N0 2 ; Nme 2 ; etc .
  • R 2 and R are D or L amino acid side chains H
  • Ri H; OH; 0CH 3 ; Cl; Br; N0 2 ; Nme 2 ; etc.
  • R 2 and R 3 are D or L amino acid side chains
  • R 2 and R 3 are D or L amino acid side chains Peptide-based bis-hydroxamate library Preferred compounds which we have found to be active are
  • the peptide-based compounds incorporate one, two or three amide bonds within the linker to act as rigid planar constraints, as well as probing hydrogen bonding interactions along the backbone of the inhibitor.
  • the addition of amino acid side chains (D or L) probes steric as well as hydrophobic, hydrogen bonding and charge-charge interactions within the receptor .
  • Extracts were electrophoresed on one-dimensional gels ( Figure 7C) and then samples of the MM96L lysates (control (A) and treated with 100 ⁇ g/ml ABHA (B) ) were subjected to two-dimensional elecrophoresis on a pH 3-10 isoelectric focusing gel followed by an 8-18% SDS polyacrylamide gel. Increases or new proteins are shown with solid arrows, and losses are shown with white arrows. The changes in protein expression which were observed were sufficiently large to identify bands, which are related to sensitivity, on one-dimensional protein gels, by comparison with resistant cells. This is illustrated in Figure 7C.
  • This approach can generate as many as 1600 compounds for the peptidic library shown above. Initially 20-30 compounds are synthesized to probe receptor space. These focused libraries are prepared using standard solid phase peptide synthesis protocols in a multiple-pin based combinatorial chemistry approach. On the basis of initial results obtained using these libraries, further compounds are subsequently made to optimise interactions and the pharmacological profile.
  • a combination of solution organic synthesis and a combinatorial non-peptide synthesis may be used to prepare a hydrocarbon library.
  • Aromatic compounds ( eg. 5 in Example 6) have much more rigid backbones than their peptidic counterparts.
  • Example 1 Comprehensive drug screening was carried out using the panel of cell lines used in Example 1. Other normal cells (neutrophils ; eosinophils ; macrophages; B lymphocytes), transformed cell lines and other cancer cell lines (colon and breast tumour cells) are used for further evaluation, if appropriate. These additional data enable elucidation of detailed selectivity profiles of cytotoxicity for each compound. Results like those in Example 1 are used to guide selection of candidates for in vivo screening. b) Metalloprotease Inhibition
  • MMPs Matrix metalloproteases
  • TMPs tissue inhibitors of metalloproteases
  • TMPs tissue inhibitors of metalloproteases
  • overexpression and activation of MMPs causes an imbalance resulting in tissue degradation. It is widely thought that MMPs are important in the growth and spread of malignant tumours, and they have also been associated with chronic diseases such arthritis and multiple sclerosis (Beckett et al , 1996) .
  • compounds such as 7 and 8 are non- selective broad-spectrum MMP inhibitors, they have been found to prevent or reduce spread or growth in models of metastasis, angiogenesis and tumour progression (Beckett et al , 1996).
  • Administration i.p. of 7 was effective against malignant ascites that formed in the peritoneal cavity in a murine xenograft model of human ovarian carcinoma.
  • these compounds inhibit many metalloenzymes , and are cytotoxic to at least some normal cells as well as a certain tumour cells.
  • the compounds of the invention are tested in metalloprotease assays, because of the known antitumour properties of hydroxamates like 7 and the more promising 8 (Beckett et al , 1996) .
  • the fundamental unit of the eukaryotic genome is the nucleosome, which is composed of DNA wrapped around a histone octamer. Histones are reversibly acetylated on the ⁇ -amino group of Lys residues. Since interactions between acetylated histones and DNA are thought to be crucial for gene expression (Wolffe, 1996), regulators of histone acetylation might be expected to affect transcription. Recent genetic, biochemical and immunological evidence suggests that histones involved with transcribed genes are more highly acetylated than histones from non- transcribed regions (Taunton et al , 1996). Inhibitors of histone deacetylase would increase the levels of histone acetylation.
  • the weak differentiating agent, butyrate (1) is known to inhibit the acetylation of histones (Kijima et al , 1993), inducing intracellular accumulation of hyperacetylated histones. Differentiation and cell cycle arrest could possibly be attributed to hyperacetylation of histones.
  • Histone hyperacetylation was examined by PAGE as described above, using MM96L melanoma cells. The results are illustrated in Figure 9, and Figure 9A shows that acetylation of histone H4 is increased following exposure of the cells to ABHA at a dose of 100 ⁇ g/ml for 24 hr . We believe that this results from inhibition of histone deacetylase .
  • Hydroxamate Sensitive Cells Western blotting of cell lysates showed that hydroxamate-sensitive cells expressed a low molecular weight form of a protein able to bind to retinoblastoma protein, designated protein RbAp48, as shown in Figure 10A, and/or expressed low levels of the full length RbAp48, as shown in Table 7.
  • Example 5 The in vivo protocol described in Example 5 was used to test the efficacy of compounds of the invention at different doses against xenografts in nude mice of the human melanoma cell line (MM96L) , an ovarian cancer cell line (JAM) , a cervical cancer (HeLa) , and the B16 mouse melanoma in C57 mice.
  • the results of these initial experiments have been used for comparative evaluation of derivatives which are expected to be much more potent and selective, in order to identify compounds with better in vivo profiles of activity than ABHA.
  • LogP % octanol soluble/% water soluble
  • LogP values are then experimentally determined by reverse phase HPLC .
  • compounds desirably have LogP values of 0 to 4, or have substituents that are known to facilitate uptake ( eg. by amine pumps, etc).
  • Bioavailabili ty Compounds which are found to be sufficiently potent and selective in vi tro, and show promise as antitumour agents in vivo in mice, are evaluated for bioavailability in animals.
  • a single dose of drug (10 mg/kg) is administered i.v. and p.o. in parallel experiments to 200-250g Sprague-Dawley rats. Serum is sampled and the parameters t ⁇ /2, T m a ⁇ . C x , F% are then calculated. For very promising candidates, further tests are performed in dogs, using similar methods.
  • Example 14 Synthesis of the Non-Peptidic Inhibitor AAHA To a 500 mL round bottom flask containing azelaic acid (20 g, 106 mmol) was added 25 mL of thionyl chloride.
  • acylated dipeptide (574 mg, 1.49 mmol) as prepared above was allowed to stir in a solution of 50% THF/water containing lithium hydroxide (125 mg, 2.97 mmol) for 30 minutes. The THF was then removed in vacuo and water (40 mL) added to the residue. Following acidification with concentrated HCl, a white precipitate was filtered, dried and carried through to the next step without further purification. Mass spectral evidence confirmed the presence of the free acid:
  • the acid (337 mg, 0.934 mmol) as prepared above was dissolved in dry THF 5 mL containing N-methylmorpholine (0.113 mL, 1.03 mmol) and isobutylchloroformate (0.133 mL, 1.03 mmol) and allowed to stir for 15 minutes. Following this, a solution containing hydroxylamine hydrochloride (130 mg, 1.87 mmol), THF (5 mL) and 5% sodium hydroxide (1.5 mL) was added in one shot and the resultant mixture allowed to stir for a further 15 minutes. The THF was then removed in vacuo and water (20 mL) added to the residue.
  • Example 16 Antiparasite Activity The activity of the compounds of the invention against unicellular parasites of three different types was examined.
  • the organisms selected were Giardia duodenalis (also known as Giardia lamblia) , Trichomonas vaginalis and Plasmodium falciparum .
  • Giardia duodenalis organisms were grown in TYI/S culture medium supplemented with 10% FCS, with and without drugs at various concentrations .
  • One of the Giardia strains, WBIB-M3 was a metronidazole-resistant strain, and was maintained in medium containing 36 ⁇ M metronidazole .
  • the minimal lethal dose (MLC) was assayed as the lowest concentration of drug at which no live parasites were present when the cultures were maintained for several days. The results are shown in Table 8.
  • Giardia duodenalis strain 106 To test in vivo activity against Giardia , three day old suckling mice were injected with Giardia duodenalis strain 106, using a dose of 10 5 trophozooytes in 15 ⁇ l PBS pH 7.3 Mice were given drugs orally on days 7 and 8 after injections, using 250 ⁇ g of ABHA or SBHA, and 265 ⁇ g of metronidazole. Giardia were harvested at day 9 for the controls and day 10 for the test mice. Small intestines of mice infected with Giardia were excised, stripped longitudinally, kept in ice-cold PBS for 30 minutes, vortexed vigourously and parasites then counted by haemocytometer .
  • ABHA was considerably more potent against human melanoma cells than HMBA. More surprising, however, was the high degree of selectivity for tumour cells compared with normal cells. This difference did not result simply from differences in the rate of cell cycling.
  • tumour cell types were sensitive to ABHA and AAHA, indicating that differentiation mechanisms, which are tissue-specific, are unlikely to be major targets for these agents. Since activity was demonstrated against transformed keratinocytes (Colo 16 and HAcat) , the invention is applicable to the treatment of conditions involving hyperproliferating keratinocytes, such as psoriasis and solar keratoses and the like. Furthermore, the ABHA-sensitive tumour line MM96L showed major differences from a resistant line in the transcriptional activation of certain genes, particularly metallothionein and SphI.
  • Enhanced dendritic morphology was the only evidence found for induction of differentiation by ABHA. For melanoma cells, this may relate to their neural crest origin. In the pigmentation pathway, loss of the TRP-1 and HMB-45 proteins and a decrease in tyrosinase activity indicated that ABHA acted as a dedifferentiating agent. That this occurs at least in part at the transcriptional level was suggested by loss of TRP-1 reporter activity and, in previous studies of HMBA (Sturm et al , 1994; Vijayasaradhi et al , 1995; Vijayasaradhi et al , 1991) , loss of TRP-1 message and protein.
  • the SV40 promoter/enhancer responds to TPA, and thus an AP-1 site in this construct may be affected by ABHA.
  • the variety of response elements in these promoters and in the HIV-LTR sequence (Edwards, 1994), coupled with lack of specificity for activation in sensitive cells, indicates that ABHA may exert many effects which are not associated with cell selectivity.
  • Some primary target (s) of the compounds of the invention have been identified. A range of possibilities needs to be considered. Hydroxamic acids have the ability to chelate zinc and other metal ions, but matrix metalloproteases are not inhibited by these compounds .
  • the metallothionein promoter response did not result from assisted uptake of zinc from the culture medium, because treatment with ABHA before zinc induction was also effective.
  • the metallothionein reporter activation by ABHA in melanoma cells may result from changes in chromatin structure, as suggested for the much less potent differentiating agent butyrate (Liu et al , 1992), enhancing transcription of a range of genes including c-fos , but repressing TRP-1 and genes activated by p53.
  • Metallothionein itself may play several roles in cellular signalling, including metal ion homeostasis (Hamer, 1986) and regulation of PKC (Ou and Ebadi , 1992), perhaps leading to alteration in regulators of the cell cycle.
  • ABHA induced a small elevation of pRB in melanoma cells treated for 12 hr . More significantly, and consistent with the observed Gl block in MM96L cells, pRB persisted at later times whereas ppRB was lost, in contrast to murine erythroleukemic cells, where ppRB levels increased (Kiyokawa et al , 1994).
  • Cyclin- dependent kinase inhibitor p21 (WAF-1) activity is associated with pRB hypophosphorylation, and is induced by p53 -dependent and -independent pathways, which may be aberrant in melanoma and other transformed cells (Vidal et al , 1995) . Activation of other types of gene could indirectly influence the outcome of treatment.
  • the immune response is considered to be an important aspect of defence against cancer, and we have found enhancement of expression of MHC class I molecules, an increase which, although slight, may assist in complete elimination of tumour cells.
  • the compounds of the invention inhibit histone deacetylation, thereby elevating levels of acetylated histones, which can interact with DNA to promote or inhibit gene expression and modulate DNA transcription.
  • the compounds useful in the present invention including ABHA, have minimal capacity to induce differentiation in neoplastic cells.
  • compounds of the present invention induce the expression of effector molecules that enhance the immune response against tumours in vivo, such as antigens of the major histocompatibility complex, and viral antigens in virus-related tumours, and we suggest that simultaneous treatment with IL-2 will overcome the down-regulation of IL-2 expression by histone deacetylation inhibitors that has been reported by Takahashi et al (1996) and thus enhance the in vivo anticancer action of these compounds .
  • Xenografts of the melanoma MM96L cells were significantly inhibited by daily treatments with 4 mg/kg ABHA, AAHA or SBHA, the first drugs of any kind to show significant activity against this cell line. Although this is a relatively high dose, other differentiating agents such as butyrate have been used safely at similar levels in the clinic to treat children with sickle cell anemia.
  • MM96L cells which were established from a metastasis, have a mutator phenotype, and are resistant to current anticancer agents in vi tro and in vivo, represent a rigorous yet probably realistic model for testing new agents . Cells cultured from the small mouse tumours that survived treatment by ABHA were still sensitive to this drug.
  • Acetylation of histone H4 was found to be induced by ABHA and AAHA, presumably by inhibition of histone deacetylase activity, as shown previously for TSA. This could be expected to profoundly alter gene expression, and may be a necessary condition for cell toxicity to occur. However, the present comparison of acetylation and deacetylation rates in intact, sensitive and resistant cells failed to find any evidence that differences in H4 acetylation could be responsible for the differential toxicity of the compounds of the invention. It is possible that other histone modifications may be involved in selectivity, or that another type of drug target may be responsible .
  • RbAp48 as a protein closely associated with resistance to ABHA, both in individual cell lines and in hybrids between sensitive and resistant cells.
  • the normal role of RbAp48 in mammalian cells has not yet been defined.
  • the RbAp48 counterpart in yeast inhibits the Ras-cAMP pathway, possibly via inhibition of PKA.
  • RbAp48 could also be involved in scaffolding or matrix attachment of chromatin to DNA (MAR regions) , shielding genes from neighbouring elements . Since the histone deacetylase inhibitor trapoxin binds RbAp48, RbAp48 is a candidate target of the compounds of the invention.
  • ABHA, AAHA, SBHA and their derivatives in combination chemotherapy to provide tumour specificity to cycle- specific drugs such as antimetabolites , including cytosine arabinoside, 5-fluorouracil, methotrexate, chlorodeoxyadenosine, etoposide, taxol (paclitaxel) , and the like, by protecting normal proliferating cells, particularly in the bone marrow and gut.
  • Regulation of apoptosis and cell division itself may be highly sensitive to the changes in nucleosomal structure and charge that result from untimely histone hyperacetylation, and to presumptive alterations in chromatin structure arising from an altered RbAp48. The same considerations may also apply to parasites.
  • the compounds of the invention have a more specific range of cellular targets than reported in the prior art for differentiating agents, resulting in selectivity for transformed and cancerous cells. Furthermore, our identification of metallothionein and SphI transcription activation, loss of G2/M blocking and reduction in expression of full-length RbAp48 have provided markers of this selectivity, which can be exploited in the treatment and prognosis of cancer.
  • the loss of contact inhibition in neoplastic and dysplastic cells and the changes in cell morphology induced by the compounds of the invention indicate that cell surface phenomena such as adhesion molecules may also play a role in their selective action.
  • the mechanism of action is more specific at the molecular level than current drugs, and is capable of exploiting the loss of cell cycle check points specifically in tumour cells.
  • Ngo L.
  • Rifkind R.A.
  • Marks P.A.

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Abstract

L'invention concerne un composé d'hydroxamate ou hydroxamique de formule (Ia) ou (Ib): HONH-[segment de liaison]-X1R1R2 or (Ic): R1R2X1-[segment de liaison]-X1R1R2, dans lesquelles X1 est un groupe polaire choisi dans le groupe constitué de -CO=O; -COR1; -CF2; -CNH2; -CNR1; -SO2-; -P(O)(OH)-; -C=S; -CSR1; -C-COR1; -C-CONR1R2 et -C-CH¿2?OH; R?1 et R2¿ sont identiques ou différents, et chacun est choisi indépendamment dans le groupe constitué de H; OH; NH¿2?; NHOH; alcényle, alkylamino, alkyloxy, arylalkyloxy ou alkyle ramifié ou linéaire, substitué ou non; aryloxy, pyridino ou aryle substitué ou non; pipéridino, cycloalkyle, cycloalkylamino, pyridineamino, 9-purine-6-amine, thiazoleamino ou arylamino substitué ou non; R?1 ou R2¿ est absent; et le segment de liaison est un groupe ayant un squelette de 5 à 9 atomes, qui peut comprendre 1, 2 ou 3 acides aminés, ou un sel, un ester ou un dérivé pharmaceutiquement acceptable dudit composé. Lesdits composés ont la capacité d'empêcher sélectivement la croissance d'une grande variété de types de cellules tumorales humaines, sans affecter la croissance des cellules normales. Ils inhibent également la croissance de parasites protozoaires.
PCT/AU1998/000431 1997-06-06 1998-06-05 Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires WO1998055449A1 (fr)

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