KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS-specific inhibitors with promising therapeutic potential.

It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene BNIP3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1a, but not p53, induces the expression of BNIP3. Overexpression of BNIP3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of BNIP3 may play a significant role during hypoxiainduced cell death. Cell Death and Differentiation (2001) 8, 367 ± 376.

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They have also served as consultants for Kura Oncology, have equity ownership in the company, and are coinventors (along with SK, TW, LS, and PR) on patent applications covering MI-3454 (PCT/US2017/022535). PR is an employee of Kura Oncology, Inc. and has a significant ownership interest in the parent of Wellspring Biosciences, Inc. FB is an employee of Kura Oncology, Inc. Kura Oncology, Inc. and the University of Michigan have filed patent applications covering MI-3454 and they hold intellectual property rights on this compound. OAW has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, and has received prior research funding from H3B Biomedicine unrelated to the current manuscript. MG receives research support from Cellectis and serves as a consultant in SeqRx.