Development of small molecule inhibitors of Mcl-1 for cancer treament

DESCRIPTION (provided by applicant): The Bcl-2 family proteins are key effectors of cancers. Recent studies indicate that Myeloma cell factor-1(Mcl-1), a member of this protein family, is a key regulator of lymphoid cancers including B-cell lymphoma, mul tiple myeloma, and chronic lymphocytic leukemia. The Bcl-2 family proteins are regulated by distinct protein- protein interactions. Manipulation of these interactions using compounds that mimic the crucial binding domain, the BH3 domain, is a valid approac h to developing oncology drugs. Efforts by commercial and academic groups have yielded several classes of compounds that target certain members of the Bcl-2 family. To date however, there has been very little effort in developing BH3 mimetics that selectiv ely target the Mcl-1 function, though there is an identified need for such compounds. Here we propose an effort to do this using a medicinal chemistry approach that will be bolstered by two novel technologies. Our starting compound, EU-517 was discovered a t Harvard Medical School in a small molecule screen for inhibitors of BH3 peptide binding to Bcl-xL. More recently derivatives that have preferential activity against Mcl-1 were made. These will be used as the starting point for developing an anti-Mcl-1 le ad compound. An innovative flexible docking model that comes from the Gerhard Wagner lab at Harvard Medical School will be used to guide lead optimization. A novel cell based assay that replicates the Mcl-1 oncogene addicted state is licensed from Dana F arber and will be used to select appropriate anti-Mcl-1 activity. This effort will receive support from academic consultants Gerhard Wagner and Anthony Letai, the inventors of the two technologies. The medicinal chemistry plan is in place and will be carri ed out by MedChem Partners Inc. in Medford MA. PUBLIC HEALTH RELEVANCE:Eutropics has assembled a strong science team to develop anti-cancer therapeutics called BH3 mimetics [4]. Recently we found anti- tumor activity of a BH3 mimetic compound that Eutropic s has now licensed from Harvard Medical School. This compound and now its derivatives have activity in inhibiting the myeloid factor-1(Mcl-1) protein in in vitro and cell based assays. Mcl-1 has been shown to be causal in certain blood cancers [9,10,11] an d is considered a viable drug target. Here we propose utilizing two novel technologies to bolster a medicinal chemistry effort to develop selective Mcl-1 inhibiting compounds.