Revolutionizing B-Cell Malignancy Treatment: The Emergence of HMPL-760 as a Potent and Selective BTK Inhibitor

Bruton’s tyrosine kinase (BTK), a Tec family member, is pivotal in B-cell receptor (BCR) signaling. BTK inhibition impedes BCR signaling, preventing B-cell proliferation and activation. First-generation BTK inhibitors, such as ibrutinib, irreversibly bind to BTK's cysteine residue (C481), but resistance often arises due to the C481S mutation. To counteract this, second-generation inhibitors like LOXO-305 and ARQ 531 are in development.

HMPL-760 was evaluated for its efficacy against both wild-type and C481S mutant BTK in biochemical assays and for selectivity using the Eurofins Cerep KinaseProfiler panel. Cellular activity was assessed in HEK293 cells with BTK variants and in human B-cell lymphoma cell lines. In vivo antitumor effects and pharmacokinetic/pharmacodynamic (PKPD) correlations were examined in HBL-1 xenograft mice with BTK mutations.

HMPL-760 potently inhibits BTK kinase activity in both BTK variants and binds reversibly. It shows high selectivity among 413 kinases. In cellular assays, HMPL-760 exhibits potent anti-proliferative effects against B-cell lymphoma cells with either BTK variant, with GI50 values ranging from 0.0015 to 0.046 μM. In human whole blood assays, it inhibits B-cell activation at nanomolar levels by suppressing CD69 expression induced by immunoglobulins in CD19+ cells. HMPL-760 demonstrates superior inhibitory potency to ARQ 531 and approximately three times that of LOXO-305 in BTK C481S cells. It also maintains longer target inhibition duration than LOXO-305 in both BTK wild type and mutant cell lines.

HMPL-760 demonstrates dose-dependent antitumor efficacy in multiple B-cell lymphoma xenograft models in mice, with complete tumor regression in most models at higher doses. Its efficacy surpasses that of LOXO-305 and ARQ 531 at comparable doses, likely due to higher drug exposure and sustained BTK phosphorylation inhibition in tumor tissues.

In conclusion, HMPL-760 is a potent, selective, reversible BTK inhibitor effective against both BTK wild type and C481S mutant. Phase 1 clinical trials for HMPL-760 in patients with relapsed/refractory B-NHL are ongoing.