Abstract 3438: Selective inhibitors of Mcl-1 with potent activity against multiple myeloma patient cells and animal xenografts.

To date most of the studies targeting apoptotic machinery have focused on inhibiting Bcl2 and Bcl_XL proteins that have shown limited clinical utility. This could be in part due to the over-expression of Myeloid Leukemia-1 (Mcl-1) that carries similar anti-apoptotic functions. Our recent evaluations of Multiple Myeloma (MM) patient derived samples have shown consistent over-expression of Mcl-1 suggesting that it is an attractive therapeutic target. We have discovered a novel druggable site in Mcl-1 protein. Using structure based drug design we have developed small molecule inhibitors (SMIs) of Mcl-1 that bind with high affinity to the BH-3 hydrophobic groove of the protein thereby displacing different pro-apoptotic partners such as Bax, Bak, Bok and Bid with activity against MM cells (IC₅₀ 5 μM) and anti-tumor activity in animal xenografts. The lead SMI (UMI-77) inhibits growth and induces apoptosis in MM cells. Molecular analysis of MM cells reveals activation of pro-apoptotic factors post UMI-77 treatment. Co-immunoprecipitation studies show that UMI-77 disrupts the Mcl-1-Bax and Mcl-1-Bak interactions. The drug synergizes with standard proteasome inhibitor Velcade (5 nM) and Carfilosimib (1 nM). In patient derived MM cells (n=45), UMI-77 inhibits growth and induces apoptosis that is concurrent with induction of Bax, Bak and enhancement in cleaved fractions of caspases 3 and 9. At similar concentrations UMI-77 does not affect normal peripheral lymphocytes. UMI-77 is well tolerated by animals at MTD (60 mg/kg i.v.). In a mice lymphoma model, oral administration of UMI-77 significantly reduced tumor growth and histological examination of tumors revealed suppression of Mcl-1 protein expression along with enhancement of pro-apoptotic markers. Our novel Mcl-1 inhibitors provide a new therapeutic option for cancers for MM that overexpress Mcl-1 that have failed standard therapies.

Citation Format: Asfar S. Azmi, Zaneta Nikolovka-Coleska, Muneer Abidi, Kelley Marsack, Ashiq Masood, Hiroshi Yano, Silvana Pregja, Jeffrey Zonder, Ramzi M. Mohammad. Selective inhibitors of Mcl-1 with potent activity against multiple myeloma patient cells and animal xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3438. doi:10.1158/1538-7445.AM2013-3438