Abstract 1641: Structure-based design and development of pyrazolopyridine-based inhibitors of Mcl-1

Abstract

Abstract The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has emerged as a promising therapeutic target. Mcl-1 is overexpressed in many human cancers which has been associated with inferior survival, poor prognosis and resistance to chemotherapies. Disruption of Mcl-1 interaction with its pro-apoptotic partners through small molecules is a viable strategy to overcome Mcl-1 mediated resistance to apoptosis. Targeting Mcl-1 protein represents a promising strategy either alone or in combination with other therapies. Applying an integrated screening approach through combining high throughput and virtual screenings, several novel chemical classes were identified as Mcl-1 inhibitors. Compound 38 with a pyrazolopyridine scaffold was selected as a promising high throughput lead for medicinal chemistry efforts. Using reported chemistry a focused library of analogs of 38 was generated. Through HSQC protein-observed NMR studies and chemical shift mapping, the binding of the lead compound 38 was characterized and confirmed to be the BH3 binding pocket of Mcl-1. Computational modeling guided by NMR studies was applied in lead optimization and rational design of more potent analogs. Structure-activity relationship was established utilizing two different competitive platforms of fluorescent polarization and surface plasmon resonance, and confirmed by HSQC NMR spectroscopy. The binding affinity of this class of compounds was improved more than twenty fold in comparison with the lead compound 38. In vitro binding, functional and cell-based assays were performed in order to determine selectivity profile against five members of Bcl-2 family, mechanism of action and cellular activity of analogs with improved potency. The obtained results show promise for further chemical modification and development of pyrazolopyridine-based inhibitors of Mcl-1. Citation Format: Fardokht A. Abulwerdi, Ahmed S.A. Mady, Andrej Perdih, Jeanne A. Stuckey, Hollis D. Showalter, Zaneta Nikolovska-Coleska. Structure-based design and development of pyrazolopyridine-based inhibitors of Mcl-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1641. doi:10.1158/1538-7445.AM2014-1641