Pethe, Kevin, Jang, Jichan, Kang, Sunhee, Park, Seijin, Ahn, Sujin, Jiricek, Jan, Jung, Juyoung, Jeon, Hee Kyoung, Cechetto, Jonathan, Christophe, Thierry, Kempf, Marie, Jackson, Mary, Lenaerts, Anne J., Pham, Ha, Jones, Victoria, Seo, Min Jung, Lee, Saeyeon, Kim, Young, Seo, Mooyoung, Seo, Jeong Jea, Ko, Yoonae, Choi, Inhee, Kim, Ryangyeo, Kim, Seyeon, Lim, SeungBin, Yim, SeungAe, Jiyoun Nam, Jiyoun Nam, Hwankyu Kang, Hwankyu Kang, Chun-Taek Oh, Chun-Taek Oh, Yoojin Cho, Yoojin Cho, Yunhee Jang, Yunhee Jang, Junghwan Kim, Junghwan Kim, Chua, Adeline, Tan, Bee Huat, Nanjundappa, Mahesh Bangalore, Rao, Srinivasa P.S., Barnes, Whitney, Wintjens, René, Walker, John, Alonso, Sylvie, Kim, Jungjun, Oh, Soohyun, Oh, Taegwon, Han, Sung-Jun, No, Zaesung, Lee, Jinhwa, Brodin, Priscille, Cho, Sang-Nae, Nam, Kiyean, 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

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