9BHI
Crystal structure of the MerTK kinase domain with SA4488
This is a non-PDB format compatible entry.
Summary for 9BHI
| Entry DOI | 10.2210/pdb9bhi/pdb |
| Descriptor | Mer tyrosine kinase domain, (5P)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-{(1R,2S)-2-[(4'-{2-[4-(2-oxoethyl)piperazin-1-yl]propan-2-yl}[1,1'-biphenyl]-4-yl)methoxy]cyclopentyl}pyridine-3-carboxamide, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | receptor tyrosine kinase, atp competitive inhibitor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38113.72 |
| Authors | Jakob, C.G.,Qui, W.,Jain, R. (deposition date: 2024-04-20, release date: 2024-10-09, Last modification date: 2024-10-23) |
| Primary citation | Yu, Y.,Jang, M.,Miyashiro, J.,Clark, R.F.,Zhu, G.D.,Gong, J.,Dai, Y.,Frey, R.R.,Penning, T.D.,Kim, H.,Lee, H.K.,Kim, J.K.,Ryu, K.M.,Park, S.J.,Yoon, T.,Li, T.,Kurnick, M.D.,Kapecki, N.J.,Li, L.,Gorman, J.V.,Montgomery, D.A.,Manaves, V.,Bromberg, K.D.,Doktor, S.Z.,Thakur, A.,Wang, J.,Smith, H.A.,Buchanan, F.G.,Ferguson, D.C.,Torrent, M.,Jakob, C.G.,Qiu, W.,Upadhyay, A.K.,Martin, R.L.,Lai, A.,Michaelides, M.R. Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor. J.Med.Chem., 67:17000-17032, 2024 Cited by PubMed Abstract: TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition. PubMed: 39283694DOI: 10.1021/acs.jmedchem.4c01450 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.07 Å) |
Structure validation
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