Structural Basis for Targeting the Folded P-Loop Conformation of c-MET

Abstract

We report here a fragment screen directed toward the c-MET kinase from which we discovered a series of inhibitors able to bind to a rare conformation of the protein in which the P-loop adopts a collapsed, or folded, arrangement. Preliminary SAR exploration led to an inhibitor (7) with nanomolar biochemical activity against c-MET and promising cell activity and kinase selectivity. These findings increase our structural understanding of the folded P-loop conformation of c-MET and provide a sound structural and chemical basis for further investigation of this underexplored yet potentially therapeutically exploitable conformational state.

Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1

“…It is well known that the phosphate-binding loop (P-loop) has a crucial role in ATP and competitive inhibitor binding and controlling the water accessibility of the binding pocket of all kinds of tyrosine kinases. , Therefore, the conformational dynamics of the P-loop is fundamental to explore rigorously to design selective inhibitors. , Recently, Collie et al suggested that two different conformations are critical for competitive inhibitors and unusual folded and extended conformation for c-Met kinases . Herein, we discuss the conformation dynamics of JAK1’s P-loop for three different phosphorylated states and that complexed with SOCS1.…”

“…74,75 Recently, Collie et al suggested that two different conformations are critical for competitive inhibitors and unusual folded and extended conformation for c-Met kinases. 76 Herein, we discuss the conformation dynamics of JAK1's P-loop for three different phosphorylated states and that complexed with SOCS1. Here, we generated the 2D FEL of the P-loop based on the P-loop rmsd value and center of mass distance between the P-loop and the conserved HRD motif (Figure 6A−F).…”

Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)

“…The ability of HPK1 to adopt the folded conformation was attributed to the unusually high number of glycine residues within its P-loop resulting in a high degree of flexibility, a feature that is absent in the LCK sequence. Literature examples suggested that stabilizing or engaging the “folded” P-loop conformation may have the potential to improve selectivity. , Hence, we hypothesized that further engagement of Gly24 and Tyr28 in the folded P-loop conformation of HPK1 may result in improvement in both potency and selectivity against our key off-target LCK and the wider kinome.…”

“…Literature examples suggested that stabilizing or engaging the "folded" P-loop conformation may have the potential to improve selectivity. 11,13 Hence, we hypothesized that further engagement of Gly24 and Tyr28 in the folded Ploop conformation of HPK1 may result in improvement in both potency and selectivity against our key off-target LCK and the wider kinome.…”

“…3-Spiro-cyclopropyl-indoline 11 demonstrated encouraging potency against HPK1 while reducing human liver microsome turnover and CYP inhibition. Expansion of the spiro-cyclopropyl ring to the cyclobutyl (12) or cyclopentyl groups (13) were also well-tolerated and offered alternative design exit vectors. In general, the spiro-indoline analogues showed a promising combination of good metabolic stability (as measured by HLM), minimal time-dependent inhibition of Selectivity expressed as the ratio of LCK K i over HPK1 K i .…”