Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode

Gummadi, V.R. and Rajagopalan, S. and Looi, C.Y. and Paydar, M. and Renukappa, G.A. and Ainan, B.R. and Krishnamurthy, N.R. and Panigrahi, S.K. and Mahasweta, K. and Raghuramachandran, S. and Rajappa, M. and Ramanathan, A. and Lakshminarasimhan, A. and Ramachandra, M. and Wong, Pooi Fong and Mustafa, Mohd Rais and Nanduri, S. and Hosahalli, S. (2013) Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode. Bioorganic & Medicinal Chemistry Letters, 23 (17). pp. 4911-4918. ISSN 0960-894X, DOI https://doi.org/10.1016/j.bmcl.2013.06.071.

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Abstract

We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7h, 7m and 7n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif. (C) 2013 Elsevier Ltd. All rights reserved.

Item Type:	Article
Funders:	UNSPECIFIED
Additional Information:	Gummadi, Venkateshwar Rao Rajagopalan, Sujatha Looi, Chung-Yeng Paydar, Mohammadjavad Renukappa, Girish Aggunda Ainan, Bharathi Raja Krishnamurthy, Narasimha Rao Panigrahi, Sunil Kumar Mahasweta, Kumari Raghuramachandran, Sangeetha Rajappa, Manoj Ramanathan, Anuradha Lakshminarasimhan, Anirudha Ramachandra, Murali Wong, Pooi-Fong Mustafa, Mohammad Rais Nanduri, Srinivas Hosahalli, Subramanya
Uncontrolled Keywords:	Anaplastic lymphoma kinase (ALK); 7-Azaindole; Anaplastic large cell lymphoma (ALCL); Cancer; Karpas299
Subjects:	R Medicine
Divisions:	Faculty of Medicine
Depositing User:	Ms Haslinda Lahuddin
Date Deposited:	11 Nov 2013 03:33
Last Modified:	18 Dec 2019 06:43
URI:	http://eprints.um.edu.my/id/eprint/8532

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