Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c02272
Abstract:
KRAS G12C is one of the most prevalent oncogenic mutations in nonsmall cell lung cancer. Herein we describe the discovery and optimization of divarasib (GDC-6036), an orally available, highly potent, and selective covalent KRAS G12C inhibitor. We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.
Discovery of Clinical Candidate IAG933, a Potent YAP-TEAD PPI Disrupter
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c03009
Abstract:
The interaction of transcriptional enhanced associate domain (TEAD) and transcriptional coactivator yes-associated protein (YAP) mediates oncogenic functions downstream of the Hippo pathway. In this report, we outline our efforts to find a potent inhibitor of this protein–protein interaction with suitable properties for clinical evaluation. We detail the medicinal chemistry program that led to the discovery of IAG933, an inhibitor with a balanced ADME profile, enabling its evaluation as a potential treatment option in clinical settings.
Design and Synthesis of BLU-654, a Potent and Selective Mutant KIT V654A Inhibitor for the Treatment of Imatinib-Resistant GIST
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5c03554
Abstract:
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma of the gastrointestinal tract, with approximately 5000 new cases annually in the USA. Approximately 80% of GIST cases are driven by activating mutations in KIT in exon 9 or 11. Resistance to present therapies like imatinib often arises from secondary KIT mutations, especially V654A (exon 13), which is the most frequent resistance mutation. Tyrosine kinase inhibitors (TKIs) currently approved for GIST can cause dose-limiting side effects due to off-target inhibition of other kinases. Herein, we report the discovery and optimization of BLU-654 (compound 18), a highly potent and kinome-sparing KIT V654A inhibitor. Preclinical efficacy studies demonstrated its prolonged antitumor activity in a KIT V654A cell-derived xenograft mouse model. BLU-654 offers a potent and selective profile suitable for combination therapy for KIT-mutant GIST patients.
