Toward Improved On-Target Safety: Discovery of Potent, Short Half-Life Macrocyclic Inhibitors of Mcl-1

Key words

Mcl-1 - beyond rule of five - macrocycles - sulfonimidamide - vinyl fluoride - allyl tetrahydrofuran

Significance

Overexpression of the pro-survival and anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) is a hallmark of many human cancers. As Mcl-1 is also expressed in cardiomyocytes, there exists the potential for on-target cardiotoxicity. ­Jerhaoui and co-workers report the design of Mcl-1 inhibitor 28 that addresses the concern of on-target cardiotoxicity via a C_max-driven approach, achieving maximal concentration (C_max) quickly and pairing that with a short half-life to avoid prolonged systemic exposure. Excellent potency and oral bioavailability were achieved, and in vivo efficacy was observed in a mouse xenograft model. Also, the potential for off-target cardiotoxicity was de-risked through in vitro profiling in stem-cell-derived cardiomyocytes.

Comment

Compound 28 is constructed through key intermediate A (reported by Amgen for the synthesis of AMG176, ref. 26 of original article), tetrahydrofuran aldehyde B and (E)-bromo fluoroalkene D. Reductive amination between core A and aldehyde B followed by debenzylation and oxidation afforded intermediate C. A nickel/chromium-mediated Nozaki–Hiyama–Kishi (NHK) coupling of aldehyde C with alkene D afforded intermediate E which was poised to undergo macrocyclization followed by sulfonimidamide formation to afford compound 28.

Publikationsverlauf

Artikel online veröffentlicht:
14. September 2023