Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker

Abstract

Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.

Mcl-1 Mediates TWEAK/Fn14-Induced Non–Small Cell Lung Cancer Survival and Therapeutic Response

“…While inhibitors of Bcl-2/Bcl-xL have been well described, specific inhibitors of Mcl-1 are now being investigated (26–28). We explored the use of a Mcl-1-specific pharmacological inhibitor designated EU-5148 (Figure S1) as an antagonist of NSCLC cell survival.…”

Small molecule Mcl-1 inhibitors for the treatment of cancer

“…(Richard, et al, 2013) A subsequent FP assay was used as a counter-screen to the primary assay to identify compounds that displayed selectivity for Mcl-1 over Bcl-X L . Evaluation of the hits identified in the HTS campaign for their synthetic tractability and quality gave the team their lead compound, the 7-hydroxyquinoline 22 (Fig.…”

Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy

“…Although the clinical development of Obatoclax has been discontinued during this study [34], our results may encourage further research into BCL2 family inhibitors, and in particular in small molecules targeting MCL1. For example, the recently identified hydroxyquinoline-derived compound 9, shows selective MCL1 inhibitory function [35]. Possible clinical studies could select patients based on results of a BH3 profiling assay, which measures dependency of any or all anti-apoptotic BCL2 proteins for cellular survival [35].…”

“…For example, the recently identified hydroxyquinoline-derived compound 9, shows selective MCL1 inhibitory function [35]. Possible clinical studies could select patients based on results of a BH3 profiling assay, which measures dependency of any or all anti-apoptotic BCL2 proteins for cellular survival [35]. …”