9NWX
Discovery of a Small Molecule ITK and Pan-TRK Kinase Inhibitor (PF-07245303) for the Potential Topical Treatment of Atopic Dermatitis
This is a non-PDB format compatible entry.
Summary for 9NWX
| Entry DOI | 10.2210/pdb9nwx/pdb |
| Descriptor | Tyrosine-protein kinase ITK/TSK, (2S)-N-methyl-N-{6-methyl-2-[(4aS,5aR)-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazol-3-yl]-1H-1,3-benzimidazol-5-yl}-2-(morpholin-4-yl)propanamide (3 entities in total) |
| Functional Keywords | kinase, inhibitor, atopic dermatitis, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 31097.57 |
| Authors | |
| Primary citation | Duffen, J.L.,Crouse, K.K.,Ji, L.,Brault, A.L.,Ford, K.,Brooks, J.,Jelinsky, S.A.,Li, Y.,Shin, J.H.,Zhao, Y.,Andreyeva, T.,Hammerman, K.,Arnold, C.,Sheldon, R.T.,Garren, J.,LaBarge, W.,Resek, A.,Volmer, J.,Bagley, S.W.,Casimiro-Garcia, A.,Chinigo, G.M.,Davoren, J.E.,Denny, R.A.,Drozda, S.,Foley, T.L.,Hicklin, R.W.,Liu, S.,Lovering, F.E.,Nedoma, N.L.,Parikh, M.D.,Strohbach, J.W.,Trujillo, J.I.,Steyn, S.J.,Nocka, K.,Hegen, M.,Vincent, F.,Lee, K.L.,Gerstenberger, B.S.,Primiano, M.J. Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Interleukin-2-inducible T cell kinase is expressed by T cells and amplifies T cell receptor-dependent signals. Interleukin-2-inducible T cell kinase deletion or inhibition reduces production of interleukin-4 and interleukin-13, key drivers of atopic dermatitis. Nerve growth factor signals via the receptor tropomyosin-related kinase A and may promote pruritus in atopic dermatitis lesions. Here we describe PF-07245303, a compound which potently inhibits interleukin-2-inducible T cell kinase and tropomyosin-related kinase family kinases capable of inhibiting T cell receptor-mediated cytokine production from CD4 and CD8 T cells and suppressing nerve growth factor-induced human basophil activation. In human skin explants, PF-07245303 demonstrates inhibition of tropomyosin-related kinase A phosphorylation, suppresses cytokine expression from T cell receptor-activated resident T cells and reverses the expression of atopic dermatitis associated genes. Topical application of PF-07245303 reduces proinflammatory and epidermal changes in a dermatitis model using female mice. By inhibiting both pathogenic inflammatory mechanisms, PF-07245303 may have therapeutic value for patients with atopic dermatitis. PubMed: 41803126DOI: 10.1038/s41467-026-70000-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.348 Å) |
Structure validation
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