Selective PTP1B inhibition by A-1331852: Uncompetitive kinetics and computational evidence for C-terminal engagement.
TL;DR
Repurposing the clinical-stage Bcl-xL BH3 mimetic A-1331852 is identified as a potent PTP1B inhibitor demonstrating a selectivity margin of at least 50-fold over TCPTP, highlighting A-1331852 as a promising starting point for developing PTP1B inhibitors designed to exploit transient, substrate-induced binding states.
Abstract
Selective inhibition of protein tyrosine phosphatase 1B (PTP1B), a well-established target in metabolic and oncological signaling pathways, is limited by its 74% active-site identity with the closely related phosphatase TCPTP. Repurposing the clinical-stage Bcl-xL BH3 mimetic A-1331852, we identify it as a potent PTP1B inhibitor demonstrating a selectivity margin of at least 50-fold over TCPTP (IC₅₀ = 4.0 μM vs >200 μM). Kinetic analysis reveals uncompetitive inhibition consistent with recognition of a substrate-induced binding site. Docking and 500 ns molecular dynamics simulations (MD) of full-length PTP1B support a putative multisite model that primarily engages the catalytic domain, with secondary stabilizing contacts at the intrinsically disordered C-terminus (ΔGbind = -42.95 kcal/mol). Comparative MD of Bcl-xL reveals a structurally distinct binding footprint, indicating that dual inhibition is driven by target-specific recognition rather than the engagement of a shared structural motif. In silico modeling of a predicted PTP1B-Bcl-xL complex suggests a coupled disorder-to-order interface bridging the PTP1B C-terminus and the Bcl-xL BH3-binding groove. Together, these results highlight A-1331852 as a promising starting point for developing PTP1B inhibitors designed to exploit transient, substrate-induced binding states.
