4CLI

Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).

Summary for 4CLI

• Entry DOI: 10.2210/pdb4cli/pdb
• Related: 4CLJ 4CMO 4CMT 4CMU
• Descriptor: ALK TYROSINE KINASE RECEPTOR, (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (3 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37315.77

Authors

McTigue, M.A.,Deng, Y.L.,Liu, W.,Brooun, A.,Stewart, A.E. (deposition date: 2014-01-14, release date: 2014-05-28, Last modification date: 2023-12-20)

Primary citation

Johnson, T.W.,Richardson, P.F.,Bailey, S.,Brooun, A.,Burke, B.J.,Collins, M.R.,Cui, J.J.,Deal, J.G.,Deng, Y.L.,Dinh, D.M.,Engstrom, L.D.,He, M.,Hoffman, J.E.,Hoffman, R.L.,Huang, Q.,Kath, J.,Kania, R.S.,Lam, H.,Lam, J.L.,Le, P.T.,Lingardo, L.,Liu, W.,Mctigue, M.A.,Palmer, C.L.,Sach, N.W.,Smeal, T.,Smith, G.L.,Stewart, A.E.,Timofeevski, S.L.,Zhu, H.,Zhu, J.,Zou, H.Y.,Edwards, M.P.
Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic Inhibitor of Alk/Ros1 with Pre-Clinical Brain Exposure and Broad Spectrum Potency Against Alk-Resistant Mutations.
J.Med.Chem., 57:4720-, 2014

PubMed Abstract: Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

PubMed: 24819116
DOI: 10.1021/JM500261Q

Experimental method

X-RAY DIFFRACTION (2.05 Å)