RT Journal Article
SR Electronic
T1 A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.31.445492
DO 10.1101/2021.05.31.445492
A1 Benjamin J. Reisman
A1 Hui Guo
A1 Haley E. Ramsey
A1 Madison T. Wright
A1 Bradley I. Reinfeld
A1 P. Brent Ferrell
A1 Gary A. Sulikowski
A1 W. Kimryn Rathmell
A1 Michael R. Savona
A1 Lars Plate
A1 John L. Rubinstein
A1 Brian O. Bachmann
YR 2021
UL http://biorxiv.org/content/early/2021/05/31/2021.05.31.445492.abstract
AB Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.Competing Interest StatementM.R.S. receives research funding from Astex, Incyte, Takeda, and TG Therapeutics; has equity with Karyopharm; serves as advisory or consultant to AbbVie, Astex, BMS, Celgene, Incyte, Karyopharm, Ryvu, Sierra Oncology, Takeda, TG Therapeutics. P.B.F currently receives research funding from Incyte, and has received research funding from Astex and Forma Therapeutics in the past.