JSF-3285, A Novel KasA Inhibitor for Tuberculosis

TY - PAT

T1 - JSF-3285, A Novel KasA Inhibitor for Tuberculosis

AU - Freundlich, Joel

AU - Alland, David

AU - Neiditch, Matthew

AU - Capodagli, Glenn

AU - Inoyama, Daigo

AU - Kumar, Pradeep

AU - Awasthi, Divya

PY - 2020/1

Y1 - 2020/1

N2 - Figure 1. Summary profile of JSF-3285: A) In vitro profile. B) X-ray crystal structure and binding constant for complex with KasA. C) In vivo profile in mouse chronic infection model. Invention Summary: New novel antibacterial drugs that treat multidrug resistant mycobacterium tuberculosis (MDR TB) represent an area of high medical need. The current tuberculosis treatment regimens involve multidrug combinations over an extended period and have associated side effects and toxicities. New TB drugs that reduce side effects and the total length of treatment may result in better patient outcomes. Through a structure-based drug design program involving >200 compounds, scientists at Rutgers have discovered and developed preclinical candidate JSF-3285. JSF-3285 was generated by optimizing analogues of DG167, a non-patented Glaxo compound. This candidate is a very potent inhibitor of KasA. The KasA enzyme of the M. tuberculosis is known to play a key role in the biosynthesis of the mycolic acid layer of the bacterium’s cell wall. This is the same pathway containing InhA which is inhibited by the first line anti-TB drug isoniazid (INH). The compound (JSF-3285) improves upon the in vitro efficacy profile of DG167 while significantly exhibiting major gains in oral exposure in mice. The compound has exhibited no significant issues regarding mouse toxicity, hERG inhibition, CYP inhibition, Ames mutagenicity, and mouse/human plasma stability and protein binding. Biochemical, biophysical, and genetic (frequency of resistance = 2.7 x 10-8 at 16X MIC compound) studies demonstrate it targets KasA (Figure 1B). JSF-3285 is prepared on a multigram scale in three steps with high yield. This gain in pharmacokinetics was evident in potent, bactericidal activity in mouse models of acute and chronic infection down to at least 5 mg/kg qd po (Figure 1C). Advantages: - First CAR-based immunotherapy to treat hepatocellular carcinoma. - Strong anti-tumor activities demonstrated both in vitro and in vivo. Market Applications: - CAR-T or CAR-NK therapy for liver cancer. - Can be used to generate "off-the-shelf" CAR-modified cell products Intellectual Property & Development Status: Patent pending. Available for licensing or collaborations.

AB - Figure 1. Summary profile of JSF-3285: A) In vitro profile. B) X-ray crystal structure and binding constant for complex with KasA. C) In vivo profile in mouse chronic infection model. Invention Summary: New novel antibacterial drugs that treat multidrug resistant mycobacterium tuberculosis (MDR TB) represent an area of high medical need. The current tuberculosis treatment regimens involve multidrug combinations over an extended period and have associated side effects and toxicities. New TB drugs that reduce side effects and the total length of treatment may result in better patient outcomes. Through a structure-based drug design program involving >200 compounds, scientists at Rutgers have discovered and developed preclinical candidate JSF-3285. JSF-3285 was generated by optimizing analogues of DG167, a non-patented Glaxo compound. This candidate is a very potent inhibitor of KasA. The KasA enzyme of the M. tuberculosis is known to play a key role in the biosynthesis of the mycolic acid layer of the bacterium’s cell wall. This is the same pathway containing InhA which is inhibited by the first line anti-TB drug isoniazid (INH). The compound (JSF-3285) improves upon the in vitro efficacy profile of DG167 while significantly exhibiting major gains in oral exposure in mice. The compound has exhibited no significant issues regarding mouse toxicity, hERG inhibition, CYP inhibition, Ames mutagenicity, and mouse/human plasma stability and protein binding. Biochemical, biophysical, and genetic (frequency of resistance = 2.7 x 10-8 at 16X MIC compound) studies demonstrate it targets KasA (Figure 1B). JSF-3285 is prepared on a multigram scale in three steps with high yield. This gain in pharmacokinetics was evident in potent, bactericidal activity in mouse models of acute and chronic infection down to at least 5 mg/kg qd po (Figure 1C). Advantages: - First CAR-based immunotherapy to treat hepatocellular carcinoma. - Strong anti-tumor activities demonstrated both in vitro and in vivo. Market Applications: - CAR-T or CAR-NK therapy for liver cancer. - Can be used to generate "off-the-shelf" CAR-modified cell products Intellectual Property & Development Status: Patent pending. Available for licensing or collaborations.

M3 - Innovation

ER -