7DXL

Fragment-based Lead Discovery of Indazole-based Compounds as AXL Kinase Inhibitors

Summary for 7DXL

• Entry DOI: 10.2210/pdb7dxl/pdb
• Descriptor: Tyrosine-protein kinase Mer, 3-[4-[6-chloranyl-5-[[(3R)-pyrrolidin-3-yl]amino]-1H-indazol-3-yl]pyrazol-1-yl]benzenecarbonitrile (3 entities in total)
• Functional Keywords: mer i650m kinase domain, axl kinase inhibitors, fragment based lead discovery, oncoprotein, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 68904.59

Authors

Anantharajan, J.,Baburajendran, N. (deposition date: 2021-01-19, release date: 2021-10-13, Last modification date: 2023-11-29)

Primary citation

Ng, P.S.,Foo, K.,Sim, S.,Wang, G.,Huang, C.,Tan, L.H.,Poulsen, A.,Liu, B.,Tee, D.H.Y.,Ahmad, N.H.B.,Wang, S.,Ke, Z.,Lee, M.A.,Kwek, Z.P.,Joy, J.,Anantharajan, J.,Baburajendran, N.,Pendharkar, V.,Manoharan, V.,Vuddagiri, S.,Sangthongpitag, K.,Hill, J.,Keller, T.H.,Hung, A.W.
Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors.
Bioorg.Med.Chem., 49:116437-116437, 2021

PubMed Abstract: AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.

PubMed: 34600239
DOI: 10.1016/j.bmc.2021.116437

Experimental method

X-RAY DIFFRACTION (3.146 Å)