35UC
Crystal structure of 2-amino-[1,2,4]triazolo[1,5-a]pyridine derivative bound to KIT
This is a non-PDB format compatible entry.
Summary for 35UC
| Entry DOI | 10.2210/pdb35uc/pdb |
| Descriptor | Mast/stem cell growth factor receptor Kit, 2-[4-(2-azanyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazol-1-yl]-~{N}-(2-fluoranyl-4-methyl-phenyl)ethanamide (3 entities in total) |
| Functional Keywords | kit inhibitor, tyrosine kinase inhibitor, gatekeeper, juxtamembrane, inflammation, allergy, chronic urticaria, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 38925.95 |
| Authors | Walker, N.P.,Jeffrey, J.L.,Blaesse, M. (deposition date: 2026-05-18, release date: 2026-09-16, Last modification date: 2026-11-04) |
| Primary citation | Moon, H.,Yan, X.,Zhu, J.,Mata, G.,Wang, Z.,Haelsig, K.T.,Schweickert, P.G.,Sivick, K.E.,Huang, H.T.,Van Abbema, A.M.,Chen, S.,Zhao, X.,Green, D.W.,Jin, L.,Young, S.W.,Walters, M.J.,Walker, N.P.,Leleti, M.R.,Powers, J.P.,Jeffrey, J.L. Leveraging Structure-Based Design to Overcome Class III RTK Off-Target Activity in the Development of Selective Wild-Type KIT Inhibitors. J.Med.Chem., 69:21335-21362, 2026 Cited by PubMed Abstract: Selective KIT inhibition is an effective strategy for treating mast cell-driven diseases, but highly conserved ATP-binding sites in class III RTKs hinder selective inhibitor design. We employed structure-guided medicinal chemistry to optimize a series of potent, selective KIT inhibitors. An initial triazolopyridine hinge-binding motif enabled potent KIT inhibition with high selectivity and, after central linker optimization, led to a "reverse" arylacetamide series with further improved potency and pharmacokinetic properties. Incorporation of a pyrazole-based linker and modification of the hinge-binding motif led to improved potency in the presence of human serum. Further tuning of the terminal aryl substituent mitigated cytochrome P450 time-dependent inhibition and improved kinome selectivity. Crystallography revealed key elements of KIT inhibition and showed that subtle modulation of linker stereoelectronic effects in the gatekeeper region can drive selectivity. These efforts yielded an optimized lead inhibitor with low-nanomolar cellular potency, high KIT selectivity, and properties favorable for chronic therapy. PubMed: 42916682DOI: 10.1021/acs.jmedchem.6c01334 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.328 Å) |
Structure validation
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