Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1

Constitutive activation of the ATF4-mediated integrated stress response (ATF4-ISR) is common in cancer and buffers the metabolic challenges imposed by rapid proliferation. However, hyperactivation of the ISR can induce apoptosis. Here we demonstrate that novel pyrazolo-thiazole derivates activate the mitochondrial protease OMA1 which subsequently induces apoptosis in diffuse large B-cell lymphoma (DLBCL) cells. Apoptosis is dependent on the OMA1 mediated cleavage of DELE1 which leads to activation of HRI and induction of the ATF4 ISR. Screening in 406 cancer cell lines identified an inverse correlation between sensitivity to OMA1 activators and expression of the mitochondrial protein FAM210B. Ectopic overexpression of FAM210B specifically blocks OMA1 activation and apoptosis induction by pyrazolo-thiazole activators in DLBCL. OMA1 activators, including the preclinical candidate BTM-3566, selectively killed ABC, GCB, and double-hit DLBCL lines and induced complete tumor regression across a panel of DLBCL patient-derived xenografts. Significance Here we describe a novel class of small molecules that activate the mitochondrial protease OMA1 and induce therapeutic responses in DLBCL preclinical models in vitro and in vivo. OMA1 activation drives apoptosis through ATF4-ISR, an orthogonal mechanism to current therapies. ### Competing Interest Statement Adrian Schwarzer: is a member of the Scientific Advisory Board of Bantam Pharmaceutical and received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Anneke Dorrie: no conflict of interest Matthias Gaestel: no conflict of interest Marc-Jens Kleppa: no conflict of interest Alexey Kotlyarov: no conflict of interest Axel Schambach: no conflict of interest Marc Liesa: co-founder and consultant of Enspire Bio LLC; received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Linsey Stiles: received contract research funding from Bantam Pharmaceuticals. Matheus Pinto: no conflict of interest. Mark Hannink: received funding in the form of a sponsored research agreement from Bantam Pharmaceuticals. Scott Slattery: received contract research funding from Bantam Pharmaceuticals. Andy Anantha: is a paid consultant to Bantam Pharmaceutical. Alan Cooper: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents WO2016196644A1, WO2018102452,WO2018102453, WO2020243582-PAMPH-20201203-0751-1, WO2020243584-PAMPH-20201203-0103 associated with the information in this paper Todd Hembrough: is a paid consultant to Bantam Pharmaceutical. Matthew Kostura: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents WO2018102452,WO2018102453 and patent application WO/2019/236936 associated with the information in this paper. Jedd Levine: is a paid consultant to Bantam Pharmaceutical and is an inventor on patents and is an inventor on patents WO2018102452 and WO2018102453 associated with the information in this paper. Michael Luther: is an employee of Bantam Pharmaceutical and is an inventor on patents WO2018102452, WO2018102453 and patent application WO/2019/236936 associated with the information in this paper. Michael Stocum: is an employee of Bantam Pharmaceutical. David Weinstock: is an employee of Merck and Co and previously held the role of Scientific Advisor to Bantam Pharmaceutical.