2. Academic Validation
  3. Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors

Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors

  • Bioorg Med Chem Lett. 2021 Jul 1;43:128058. doi: 10.1016/j.bmcl.2021.128058.
Veronica Calvo 1,  David Surguladze 1,  An-Hu Li 1,  Matthew D Surman 2,  Srikanth Malibhatla 3,  Madhavarao Bandaru 3,  Suresh Krishna Jonnalagadda 3,  Ravi Adarasandi 3,  Madhusudhan Velmala 3,  Durga Rama Prasad Singireddi 3,  Mahendar Velpuri 3,  Bhaskar Reddy Nareddy 3,  Visweswara Sastry 3,  Chiranjeevi Mandati 3,  Rambabu Guguloth 3,  Shapi Siddiqui 3,  Basanagoud S Patil 3,  Elena Chad 4,  Jennifer Wolfley 4,  Jennifer Gasparek 4,  Kirsten Feldman 4,  Matthew Betzenhauser 4,  Brent Wiens 4,  Mary Koszelak-Rosenblum 4,  Guangyu Zhu 4,  Hongwen Du 5,  Alan C Rigby 1,  Mark J Mulvihill 6
Affiliations

Affiliations

  • 1 HiberCell Inc. 619 West 54th Street, New York, NY 10019, USA.
  • 2 AMRI, 26 Corporate Circle, Albany, NY 12203, USA.
  • 3 AMRI, Plot #9, MN Park, Turkapally, Shameerpet, Genome Valley, RR District, Hyderabad 500078, India.
  • 4 AMRI, 1001 Main Street, Buffalo, NY 14203, USA.
  • 5 Pharmaron Beijing, Co. Ltd., No. 6, TaiHe Road, BDA, Beijing 100176, China.
  • 6 HiberCell Inc. 619 West 54th Street, New York, NY 10019, USA. Electronic address: mmulvihill@hibercell.com.
PMID: 33895276 DOI: 10.1016/j.bmcl.2021.128058
Abstract

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged Cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.

Keywords

786-O cell; Cancer; Efficacy; Inhibitor; Kinase; Orally bioavailable; PERK; Structure–activity-relationships (SAR); UPR.

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