Mae Saldajeno-Concar

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

Christopher J. Schulze, Kyle J. Seamon, Yulei Zhao, Yu Chi Yang et autres

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant …

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Abstract 1273: Discovery of a potent, selective, and orally bioavailable SOS1 inhibitor, RMC-023, an in vivo tool compound that blocks RAS activation via disruption of the RAS-SOS1 interaction

Andreas Buckl, Elsa Quintana, Grace J. Lee, Nataliya Tovbis Shifrin et autres

Abstract The guanine nucleotide exchange factor (GEF) protein SOS1 activates RAS by promoting its conversion from the GDP-bound RAS(OFF) state to the GTP-bound RAS(ON) state. SOS1 catalyzes or accelerates this nucleotide exchange reaction in response to upstream signals conveyed by a range …

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A06 Tri-complex Inhibitors of the Oncogenic, GTP-Bound Form of KRASG12C Overcome RTK-Mediated Escape Mechanisms and Drive Tumor Regressions in Preclinical Models of NSCLC

R. Jeremy Nichols, Chris J. Schulze, Alun Bermingham, Tiffany J. Choy et autres

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Abstract PR10: Tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in vivo

Christopher J. Schulze, Alun Bermingham, Tiffany J. Choy, James Cregg et autres

Abstract RAS proteins are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant RAS proteins are found in approximately one-third of human cancers, and exist predominantly in the GTP-bound state, leading to excessive downstream signaling via interaction with …

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Abstract 4877: Allosteric inhibition of SHP2 variants containing cancer-associated activating mutations

David P. Wildes, Naing Aay, Andreas Buckl, Daphne Hsieh et autres

Abstract SHP2 (PTPN11) is a non-receptor protein tyrosine phosphatase and scaffold protein that functions in multiple signal transduction pathways. Genetic and pharmacologic evidence supports a role for SHP2 in driving the proliferation of cancer cells dependent upon a range of activated RTKs, …

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Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity

Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar et autres

Abstract Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS …

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