EP-3766510-B1 - CONJUGATES AND PRODRUGS FOR USE IN THE TREATMENT OF CANCER AND INFLAMMATORY DISEASES

Inventors

• PAPOT, Sébastien
• OPALINSKI, ISABELLE
• RENOUX, BRIGITTE
• LEGIGAN, Thibaut

Dates

Publication Date

20260513

Application Date

20150206

Claims (11)

1. A conjugate of general formula (I): wherein: - A represents dolastatin 10, auristatin PE and auristatin E, - L represents a maleimidocaproyl moiety, - G comprises and preferably represents a glucuronyl radical, - Y represents an electron-withdrawing group, in particular selected from NO 2 , CF 3 and a halogen, - R 1 and R 2 represent, independently of one another, H or a linear or branched, saturated or unsaturated C 1 to C 10 alkyl radical, - Z represents a hydrocarbon spacer radical comprising covalent bond functions at each of its ends, - X represents -O- or -NR 3 COO-, where R 3 may represent a hydrogen atom or a linear or branched, saturated or unsaturated C 1 to C 10 alkyl radical, the bond with the radical G being provided by the oxygen atom (-O) and/or a pharmaceutically acceptable salt thereof.
2. Conjugate according to claim 1, wherein Y represents NO 2 in the ortho position to X, and R 1 and R 2 represent H.
3. A conjugate according to any one of claims 1 to 5, wherein Z represents a radical Z 1 -Z 2 -(Z 3 ) m , wherein: - m is 0 or 1 - Z 1 represents an L-click linking function between the carbon bearing the functions R 1 and R 2 , and the function Z 2 , - Z 2 represents a linear or branched, saturated or unsaturated C 1 to C 10 alkylene group, optionally interrupted by one or more heteroatoms selected from O or N, a glycosylated radical, an O-(CHR 4 -CHR 5 -O-) P or N-(CHR 4 -CHR 5 -O-) P in which p is a natural number ranging from 1 to 20, and R 4 and R 5 are, independently of one another, H or CH 3 , provided that R 4 and R 5 do not simultaneously represent CH 3 , a group derived from an amino acid or a peptide, or a combination of these groups, one end of Z 2 forming a covalent bond with L, either directly via an ether function or indirectly via a Z 3 function, - Z 3 represents an ester, amide, ether, carbamate or carbonate function established between the Z 2 function and the L radical.
4. A conjugate according to any one of claims 1 to 6, having the following formula (III): where p is as defined in claim 3, a pharmaceutically acceptable salt thereof.
5. A prodrug comprising at least one molecule of the conjugate according to any one of claims 1 to 4, said molecule of the conjugate being bound by a covalent bond to an albumin molecule or a fragment thereof.
6. A prodrug according to claim 5, wherein the covalent bond is formed with the thiol group of cysteine at position 34 of endogenous albumin.
7. A prodrug according to one of claims 5 and 6, which has the formula s the following formula (VII): where p is as defined in claim 3, a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising at least an effective amount of at least one conjugate as defined in any of claims 1 to 10 or a prodrug as defined in any of claims 5 to 7.
9. A conjugate according to any one of claims 1 to 4, for use in the prevention and/or treatment of cancer and/or an inflammatory disease.
10. A prodrug according to any of claims 5 to 7, or for use in the prevention and/or treatment of cancer and/or an inflammatory disease.
11. A composition according to claim 8, for use in the prevention and/or treatment of cancer and/or an inflammatory disease.

Description

FIELD OF INVENTION The present invention relates to the field of cancer and inflammatory diseases. More particularly, the present invention aims to provide new conjugated forms of active ingredients belonging to the dolastatin family. TECHNOLOGICAL BACKGROUND Cancer and inflammatory diseases are among the most common pathologies today. In particular, cancer is now one of the leading causes of death in France and most industrialized countries. Among the various treatment options, chemotherapy is the only one effective against circulating tumors, such as lymphomas and leukemias, and metastases. Among the potential agents for chemotherapy are certain natural peptide compounds, such as dolastatin 10, a linear natural compound derived from marine sources, composed of four amino acids, three of which are specific to it. Synthetic derivatives of dolastatin 10 are also available and preferred today. These include, in particular, auristatin PE, auristatin E, and monomethyl auristatin E (MMAE). Dolastatin, auristatin E, and their derivatives have the property of inhibiting tubulin polymerization and thus preventing cell division (antimitotic). However, these dolastatin-based drugs, like other clinically used anticancer agents, unfortunately lack satisfactory selectivity for tumor cells. In fact, they also target healthy tissues. This non-selective destruction leads to severe side effects and, in most cases, results in premature discontinuation of treatment. The development of new anticancer agents capable of selectively destroying tumors without affecting healthy organs is therefore of major interest in the fight against cancer. One approach to overcome this lack of selectivity relies on the development of conjugates of these active ingredients. These conjugates, also called prodrugs, are most often obtained by grafting the active ingredient with an entity whose functions are to inactivate it in its prodrug form, to transport it to the target tissues or cells, to promote its release there, and thus restore its curative biological activity. This approach is based more specifically on the observation of characteristics unique to tumor tissues. For example, it is known that the tumor microenvironment differs from healthy tissues by a more acidic pH, a higher reducing potential, increased permeability to macromolecules, and the presence of a relatively high concentration of certain enzymes, such as β-glucuronidase. Similarly, it has been shown that diseased tissues are distinguished from healthy tissues by the fact that malignant cells overexpress on their surface membrane receptors or antigens that differentiate them from healthy cells, such as folic acid receptors or the CD33 antigen. Consequently, derivatives of conventional assets have already been developed to take advantage of these differences in order to increase, in particular, their selectivity for tumor cells. Thus, monomethyl auristatin E (MMAE) was conjugated to an anti-CD30 antibody via a cleavable arm ( US 7,829,531 ). However, such a conjugate exhibits too high a specificity towards its target and proves to be of little or no effectiveness against cancers and/or non-CD30-dependent inflammatory diseases. Teming et al. (2006, Bioconjugate Chem ) have conjugated a molecule of monomethyl auristatin E (MMAE) to an albumin motif, via a cleavable linker, in order to target tumor tissues. More recently, Legigan et al. (2013, Eur. J. Med. Chem. ) And Tranoy-Opalinski et al. (2014, Eur. J. Med. Chem. ) conjugated a molecule of monomethyl auristatin E (MMAE) to a glucuronyl motif via a self-reactive arm. This conjugated form of MMAE, also called the prodrug, is inactive, and only cleavage at the tumor site by β-glucuronidases, predominantly extracellular, allows MMAE to exert its antimitotic biological activity. However, rapid elimination of this prodrug by the kidneys is observed. The half-life of this prodrug is significantly reduced, it follows that it is necessary to increase the dosage, which is accompanied by deleterious side effects. Legigan et al. (2012, Angew. Chem. Int. Ed. They also proposed a monomethyl auristatin E (MMAE) bi-functionalized with a galactoside group and a group that binds to folic acid receptors, both groups being carried by a self-reactive arm. However, this prodrug requires a cellular internalization step before being cleaved by an intracellular β-galactosidase and releasing monomethyl auristatin E (MMAE). Consequently, although these pro-drug forms of monomethyl auristatin E are specifically delivered to the tumor site, their cytotoxic efficacy remains relative, and does not allow for the consideration of an effective clinical treatment of a tumor. Therefore, there remains a need for pro-drugs from the dolastatin family, capable of delivering this type of active ingredient with very high specificity and, in inactive form, to diseased tissues or cells. There is also a need for pro-drugs from the dolastatin family whose cytotoxicity is