2. Academic Validation
  3. Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis

Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis

  • Bioorg Med Chem Lett. 2024 Nov 12:130026. doi: 10.1016/j.bmcl.2024.130026.
Yuebiao Zhou 1,  Ignacio Aliagas 2,  Shumei Wang 2,  Chun Sing Li 3,  Zhiguo Liu 3,  Christine M Bowman 2,  Daniel J Burdick 2,  Kevin R Clark 2,  Tahnee J Dening 2,  John Flygare 2,  Anjani Ganti 2,  Hany S Girgis 2,  Emily J Hanan 2,  Seth F Harris 2,  Chloe Hu 2,  Sharookh B Kapadia 2,  Michael F T Koehler 2,  Tommy Lai 3,  Jun Liang 2,  Xingrong Liu 2,  Fang Ma 2,  Jialin Mao 2,  Jeremy Nicolai 2,  Jessica Sims 2,  Savita Unhayaker 2,  John Wai 3,  Xiaojing Wang 2,  Ping Wu 2,  Yiming Xu 2,  Chun-Wan Yen 2,  Renwei Zhang 3,  Torben F Elfert 2,  Man-Wah Tan 2,  Eric M Kofoed 2,  Terry D Crawford 4
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: zhou.yuebiao@gene.com.
  • 2 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3 Wuxi Apptec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
  • 4 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: terrydc@gene.com.
PMID: 39536836 DOI: 10.1016/j.bmcl.2024.130026
Abstract

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb Infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the Enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel Antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.

Keywords

Drug discovery; GuaB; Infectious disease; Mycobacterium tuberculosis; Structure-based drug design; Tuberculosis.

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