Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis

Wang, Heng1; Bi, Jing2; Zhang, Yuan1; Pan, Miaomiao1; Guo, Qinglong2; Xiao, Genhui1; Cui, Yumeng1; Hu, Song1; Chan, Chi Kin1; Yuan, Ying1; Kaneko, Takushi3; Zhang, Guoliang2; Chen, Shawn1

2022-09-01

10.1021/acsinfecdis.2c00278

ACS Infectious Diseases   Impact Factor & Quartile

2373-8227

ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are antibacterial and anticancer targets including human kinases acted on by most of the successful drugs. In search of new chemotherapeutics for tuberculosis (TB), we screened repurposing compounds against the essential glutamine synthase (GlnA1) of Mycobacterium tuberculosis (Mtb) and identified linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR as a potent GlnA1 inhibitor. Linsitinib has direct antimycobacterial activity. Biochemical, molecular modeling, and target engagement analyses revealed the inhibition is ATP-competitive and specific in Mtb. Linsitinib also improves autophagy flux in both Mtb-infected and uninfected THP1 macrophages, as demonstrated by the decreased p-mTOR and p62 and the increased lipid-bound LC3B-II and autophagosome forming puncta. Linsitinib-mediated autophagy reduces intracellular growth of wild-type and isoniazid-resistant Mtb alone or in combination with bedaquiline. We have demonstrated that an IGF-IR/IR inhibitor can potentially be used to treat TB. Our study reinforces the concept of targeting ATP-dependent enzymes for novel anti-TB therapy.

M tuberculosis glutamine synthetase IGF1R IR inhibitor autophagy ATP-dependent enzyme

SCI

English

Corresponding

Pharmacology & Pharmacy ; Infectious Diseases

Chemistry, Medicinal ; Infectious Diseases

WOS:000854008300001

AMER CHEMICAL SOC

Web of Science

1.Global Hlth Drug Discovery Inst, Beijing 100192, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Guangdong Prov Clin Res Ctr TB, Shenzhen 518112, Peoples R China
3.Global Alliance TB Drug Dev, New York, NY 10005 USA

Wang, Heng,Bi, Jing,Zhang, Yuan,et al. Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis[J]. ACS Infectious Diseases,2022.

Wang, Heng.,Bi, Jing.,Zhang, Yuan.,Pan, Miaomiao.,Guo, Qinglong.,...&Chen, Shawn.(2022).Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis.ACS Infectious Diseases.

Wang, Heng,et al."Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis".ACS Infectious Diseases (2022).