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Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis.

Pethe, Kevin and Jang, Jichan and Kang, Sunhee and Park, Seijin and Ahn, Sujin and Jiricek, Jan and Jung, Juyoung and Jeon, Hee Kyoung and Cechetto, Jonathan and Christophe, Thierry and Kempf, Marie and Jackson, Mary and Lenaerts, Anne J. and Pham, Ha and Jones, Victoria and Seo, Min Jung and Lee, Saeyeon and Kim, Young and Seo, Mooyoung and Seo, Jeong Jea and Ko, Yoonae and Choi, Inhee and Kim, Ryangyeo and Kim, Seyeon and Lim, SeungBin and Yim, SeungAe and Jiyoun Nam, Jiyoun Nam and Hwankyu Kang, Hwankyu Kang and Chun-Taek Oh, Chun-Taek Oh and Yoojin Cho, Yoojin Cho and Yunhee Jang, Yunhee Jang and Junghwan Kim, Junghwan Kim and Chua, Adeline and Tan, Bee Huat and Nanjundappa, Mahesh Bangalore and Rao, Srinivasa P.S. and Barnes, Whitney and Wintjens, René and Walker, John and Alonso, Sylvie and Kim, Jungjun and Oh, Soohyun and Oh, Taegwon and Han, Sung-Jun and No, Zaesung and Lee, Jinhwa and Brodin, Priscille and Cho, Sang-Nae and Nam, Kiyean and Bifani, Juan Pablo and Kim, Jaeseung (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine, 19 (9). pp. 1157-1160. ISSN 1078-8956

Official URL: http://www.nature.com

Abstract

New prophylactic and therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of extensively-drug resistant form of the disease. During the course of a high-content chemical screen, ImidazoPyridine Amides (IPA) were identified as a promising class of anti-tubercular agents. The optimized IPA compound Q203 inhibits the growth of multi- and extensively-drug resistant clinical isolates of M. tuberculosis in the low nanomolar range. Q203 was efficacious in vivo at a dose below 1mg/kg, making this compound one of the most potent discovered up to date. In addition, it shows pharmacokinetic and safety profiles compatible with once daily dosing. A reverse genetic approach identifies the ubiquinol cytochrome C reductase (QcrB, Rv2196) as the target of Q203. Mode of action studies revealed that Q203 inhibits the process of ATP synthesis in both replicating and hypoxic non-replicating M. tuberculosis. Altogether, our data indicates that Q203 is a promising clinical candidate for the treatment of tuberculosis.

Item Type: Article
Additional Information: Report on a new anti-tubercular. Work done in collaboration with the Institut Pasteur. Korea. Patent of the molecule involved (Q203) is held by collaborators, Institut Pasteur, Korea, not Novartis.
Keywords: Tuberculosis, anti-tubercular
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/8886

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