Julian Downward: Compounds that block the interaction of RAS proteins with PI3-kinase
Julian Downward, Cancer biologist at the Francis Crick Institute, shared a post on X about a recent paper by him and colleagues published in bioRxiv:
“Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2”
Authors: Joseph Klebba, Nilotpal Roy, Steffen Bernard, Julian Downward, Matthew Patricelli et al.
“Happy to report the posting of a new study on compounds that block the interaction of RAS proteins with PI 3-kinase PIK3CA from Vividion Therapeutics, in collaboration with Francis Crick Institute.
This manuscript focuses on the discovery and characterization of covalent ligands binding a unique cysteine (C242) in the RAS binding domain of PIK3CA, and that block RAS mediated amplification of PI3Kα signaling.
These compounds inhibit the growth of KRAS mutant cancers in vitro and in preclinical models, especially when combined with MEK or KRAS G12C inhibitors. Unexpectedly, they are also very potent against HER2 over-expressing cancers.
These RAS/PI3K interaction blockers do not disrupt glucose homeostasis or insulin levels in the blood, and thus avoid toxicities associated previously with PI 3-kinase inhibitors.
BridgeBio Oncology Therapeutics has recently launched a clinical trial with BBO-10203, a PI3Kα:RAS breaker that binds to PI3K at the same site as the Vividion compounds, but with distinct mechanism of action.
These agents add a new front to targeting RAS driver oncogenes in cancer, focusing on the alternative RAS effector pathway PI3K, rather than the RAF pathway. Thanks to Joe Klebba, Matt Patricelli and the whole Vivdion team for bringing my lab into this fantastic collaboration!”
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