Author: Zorn, Kimberley M. ; Neiditch, Matthew B. ; Puhl, Ana C. ; Freundlich, Joel S. ; Vignaux, Patricia A. ; Capodagli, Glenn C. ; Lane, Thomas R. ; Ekins, Sean

Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and is a deadly disease resulting in the deaths of approximately 1.5 million people with 10 million infections reported in 2018. Recently, a key condensation step in the synthesis of mycolic acids was shown to require β-ketoacyl-ACP synthase (KasA). A crystal structure of KasA with the small molecule DG167 was recently described, which provided a starting point for using computational structure-based approaches to identify additional molecules binding to this protein. We now describe structure-based pharmacophores, docking and machine learning studies with Assay Central as a computational tool for the identification of small molecules targeting KasA. We then tested these compounds using nanoscale differential scanning fluorimetry and microscale thermophoresis. Of note, we identified several molecules including the Food and Drug Administration (FDA)-approved drugs sildenafil and flubendazole with K _d values between 30-40 μM. This may provide additional starting points for further optimization.

01 May 2020·Cell Chemical BiologyQ1 · BIOLOGY

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Q1 · BIOLOGY

Article

Author: Ahn, Yong-Mo ; Mina, Marizel ; Ho Liang, Hsin Pin ; Capodagli, Glenn C ; Kumar, Pradeep ; Inoyama, Daigo ; Perlin, David S ; Neiditch, Matthew B ; Sukheja, Paridhi ; Freundlich, Joel S ; Park, Steven ; Li, Shao-Gang ; Grady, Courtney ; Wang, Xin ; Jadhav, Ravindra ; Shrestha, Riju ; Alland, David ; Awasthi, Divya ; Li, Liping ; Connell, Nancy ; Richmann, Todd ; Tsotetsi, Kholiswa ; Zimmerman, Matthew ; Russo, Riccardo ; Dartois, Véronique

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

21 Dec 2018·mBio

Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

Article

Author: Morris, Roxanne ; Perryman, Alexander L. ; Connell, Nancy ; Capodagli, Glenn C. ; Dartois, Véronique ; Salgame, Padmini ; Li, Shao-Gang ; Rhee, Kyu Y. ; Zimmerman, Matthew ; Porter, Gene ; Kumar, Pradeep ; Verma, Sheetal ; Sukheja, Paridhi ; Gupta, Aditi ; Awasthi, Divya ; Maharaja, Karishma ; Russo, Riccardo ; Alland, David ; Ho Liang, Hsin Pin ; Shrestha, Riju ; Mina, Marizel ; Singleton, Eric ; Husain, Seema ; Inoyama, Daigo ; Ekins, Sean ; Rasic, George ; Wang, Zhe ; Sarathy, Jansy ; Neiditch, Matthew B. ; Richmann, Todd ; Agnihotri, Gautam ; Freundlich, Joel S. ; Soteropoulos, Patricia

Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis, Miliary	Discovery	United States	Collaborations Pharmaceuticals, Inc.	-

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