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

Kevin Pethe, Pablo Bifani, Jichan Jang, Sunhee Kang, Seijin Park, Sujin Ahn, Jan Jiricek, Juyoung Jung, Hee Kyoung Jeon, Jonathan Cechetto, Thierry Christophe, Honggun Lee, Marie Kempf, Mary Jackson, Anne J. Lenaerts, Ha Pham, Victoria Jones, Min Jung Seo, Young Mi Kim, Mooyoung SeoJeong Jea Seo, Dongsik Park, Yoonae Ko, Inhee Choi, Ryangyeo Kim, Se Yeon Kim, Seungbin Lim, Seung Ae Yim, Jiyoun Nam, Hwankyu Kang, Haejin Kwon, Chun Taek Oh, Yoojin Cho, Yunhee Jang, Junghwan Kim, Adeline Chua, Bee Huat Tan, Mahesh B. Nanjundappa, Srinivasa P.S. Rao, Whitney S. Barnes, René Wintjens, John R. Walker, Sylvie Alonso, Saeyeon Lee, Jungjun Kim, Soohyun Oh, Taegwon Oh, Ulf Nehrbass, Sung Jun Han, Zaesung No, Jinhwa Lee, Priscille Brodin, Sang Nae Cho, Kiyean Nam, Jaeseung Kim

Research output: Contribution to journalArticle

257 Citations (Scopus)

Abstract

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3-5, several of which are currently in clinical trials6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

Original languageEnglish
Pages (from-to)1157-1160
Number of pages4
JournalNature Medicine
Volume19
Issue number9
DOIs
Publication statusPublished - 2013 Sep 1

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Tuberculosis
Mycobacterium tuberculosis
Amides
Pharmaceutical Preparations
Multidrug-Resistant Tuberculosis
Pharmacokinetics
Electron Transport Complex III
Reducing Agents
Pandemics
Public health
Drug Discovery
Therapeutics
Growth
Drug Resistance
Culture Media
Public Health
Display devices
Body Weight
Safety
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pethe, K., Bifani, P., Jang, J., Kang, S., Park, S., Ahn, S., ... Kim, J. (2013). Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine, 19(9), 1157-1160. https://doi.org/10.1038/nm.3262
Pethe, Kevin ; Bifani, Pablo ; Jang, Jichan ; Kang, Sunhee ; Park, Seijin ; Ahn, Sujin ; Jiricek, Jan ; Jung, Juyoung ; Jeon, Hee Kyoung ; Cechetto, Jonathan ; Christophe, Thierry ; Lee, Honggun ; Kempf, Marie ; Jackson, Mary ; Lenaerts, Anne J. ; Pham, Ha ; Jones, Victoria ; Seo, Min Jung ; Kim, Young Mi ; Seo, Mooyoung ; Seo, Jeong Jea ; Park, Dongsik ; Ko, Yoonae ; Choi, Inhee ; Kim, Ryangyeo ; Kim, Se Yeon ; Lim, Seungbin ; Yim, Seung Ae ; Nam, Jiyoun ; Kang, Hwankyu ; Kwon, Haejin ; Oh, Chun Taek ; Cho, Yoojin ; Jang, Yunhee ; Kim, Junghwan ; Chua, Adeline ; Tan, Bee Huat ; Nanjundappa, Mahesh B. ; Rao, Srinivasa P.S. ; Barnes, Whitney S. ; Wintjens, René ; Walker, John R. ; Alonso, Sylvie ; Lee, Saeyeon ; Kim, Jungjun ; Oh, Soohyun ; Oh, Taegwon ; Nehrbass, Ulf ; Han, Sung Jun ; No, Zaesung ; Lee, Jinhwa ; Brodin, Priscille ; Cho, Sang Nae ; Nam, Kiyean ; Kim, Jaeseung. / Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. In: Nature Medicine. 2013 ; Vol. 19, No. 9. pp. 1157-1160.
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abstract = "New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3-5, several of which are currently in clinical trials6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.",
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Pethe, K, Bifani, P, Jang, J, Kang, S, Park, S, Ahn, S, Jiricek, J, Jung, J, Jeon, HK, Cechetto, J, Christophe, T, Lee, H, Kempf, M, Jackson, M, Lenaerts, AJ, Pham, H, Jones, V, Seo, MJ, Kim, YM, Seo, M, Seo, JJ, Park, D, Ko, Y, Choi, I, Kim, R, Kim, SY, Lim, S, Yim, SA, Nam, J, Kang, H, Kwon, H, Oh, CT, Cho, Y, Jang, Y, Kim, J, Chua, A, Tan, BH, Nanjundappa, MB, Rao, SPS, Barnes, WS, Wintjens, R, Walker, JR, Alonso, S, Lee, S, Kim, J, Oh, S, Oh, T, Nehrbass, U, Han, SJ, No, Z, Lee, J, Brodin, P, Cho, SN, Nam, K & Kim, J 2013, 'Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis', Nature Medicine, vol. 19, no. 9, pp. 1157-1160. https://doi.org/10.1038/nm.3262

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. / Pethe, Kevin; Bifani, Pablo; Jang, Jichan; Kang, Sunhee; Park, Seijin; Ahn, Sujin; Jiricek, Jan; Jung, Juyoung; Jeon, Hee Kyoung; Cechetto, Jonathan; Christophe, Thierry; Lee, Honggun; Kempf, Marie; Jackson, Mary; Lenaerts, Anne J.; Pham, Ha; Jones, Victoria; Seo, Min Jung; Kim, Young Mi; Seo, Mooyoung; Seo, Jeong Jea; Park, Dongsik; Ko, Yoonae; Choi, Inhee; Kim, Ryangyeo; Kim, Se Yeon; Lim, Seungbin; Yim, Seung Ae; Nam, Jiyoun; Kang, Hwankyu; Kwon, Haejin; Oh, Chun Taek; Cho, Yoojin; Jang, Yunhee; Kim, Junghwan; Chua, Adeline; Tan, Bee Huat; Nanjundappa, Mahesh B.; Rao, Srinivasa P.S.; Barnes, Whitney S.; Wintjens, René; Walker, John R.; Alonso, Sylvie; Lee, Saeyeon; Kim, Jungjun; Oh, Soohyun; Oh, Taegwon; Nehrbass, Ulf; Han, Sung Jun; No, Zaesung; Lee, Jinhwa; Brodin, Priscille; Cho, Sang Nae; Nam, Kiyean; Kim, Jaeseung.

In: Nature Medicine, Vol. 19, No. 9, 01.09.2013, p. 1157-1160.

Research output: Contribution to journalArticle

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AU - Christophe, Thierry

AU - Lee, Honggun

AU - Kempf, Marie

AU - Jackson, Mary

AU - Lenaerts, Anne J.

AU - Pham, Ha

AU - Jones, Victoria

AU - Seo, Min Jung

AU - Kim, Young Mi

AU - Seo, Mooyoung

AU - Seo, Jeong Jea

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AU - Ko, Yoonae

AU - Choi, Inhee

AU - Kim, Ryangyeo

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AU - Oh, Chun Taek

AU - Cho, Yoojin

AU - Jang, Yunhee

AU - Kim, Junghwan

AU - Chua, Adeline

AU - Tan, Bee Huat

AU - Nanjundappa, Mahesh B.

AU - Rao, Srinivasa P.S.

AU - Barnes, Whitney S.

AU - Wintjens, René

AU - Walker, John R.

AU - Alonso, Sylvie

AU - Lee, Saeyeon

AU - Kim, Jungjun

AU - Oh, Soohyun

AU - Oh, Taegwon

AU - Nehrbass, Ulf

AU - Han, Sung Jun

AU - No, Zaesung

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AU - Brodin, Priscille

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Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine. 2013 Sep 1;19(9):1157-1160. https://doi.org/10.1038/nm.3262