GNE-6893 / Roche - LARVOL DELTA

Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1. (PubMed, ACS Med Chem Lett) - "These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong in vitro augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 μM), a favorable in vitro safety profile, and good projected human pharmacokinetics."

Journal • Oncology

Convergent synthesis of HPK1 inhibitor GNE-6893 via palladium-catalyzed functionalization of a tetrasubstituted isoquinoline (ACS-Fall 2023) - "The production of the final active pharmaceutical ingredient (API) was achieved in 33% overall yield and 98 A% HPLC purity by a one-pot process of global deprotection, pH adjustment, crystallization, and isolation. Green chemistry practices were implemented in the process development of GNE-6893 (1) by utilizing a biocatalytic resolution to produce (3R,4S)-4-methyltetrahydrofuran-3-ol and replacing toxic triphosgene with a safer alternative, disuccinimidyl carbonate (DSC), to construct the carbamate penultimate intermediate to API."

GNE-6893, a novel orally available HPK1 inhibitor, described by Genentech researchers (Bioworld) - "Genentech Inc. presented data on structure-based lead optimization of orally bioavailable hematopoietic progenitor kinase 1 (HPK1) inhibitors. HPK1 is a negative regulator of T-cell receptor signaling in human T cells and target inhibition significantly increases cytokine production, such as IFN-gamma, TNF-alpha and IL-2, and T-cell proliferation, suggesting HPK1 inhibition as an intracellular T-cell target for cancer immunotherapy."

Clinical • Oncology