Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-X_L

Abstract

Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-XL and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

“…HldE-K inhibitors [290] 7 Inhibitors of BclXL [291] Firooznia et al, have synthesized BTA-acetamide derivative synthesized evaluated for their selectivity against the A 2A and A 1 receptors. Antagonists of the A 2B receptorhave been used as potential thearapeutic agents in models of diabetes, asthma, COPD, and pulmonary fibrosis.…”

Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer

“…These include dual BCL-X L /MCL-1 inhibitors 69 and BCL-X L -selective inhibitors, WEHI-539, 70,71 A-1155463 72 and A-1331852. 73 The latter two compounds appear to synergize with docetaxel without inducing neutropenia observed with the BCL-2/BCL-X L inhibitor navitoclax.…”

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

“…16,17 Optimization led to the identification of WEHI-539 (3), which demonstrated selective and mechanism-based cell killing in mouse embryo fibroblast (MEF) cells engineered to be dependent on BCL-X L via loss of MCL-1 (mcl-1…”