Seshu K Kanneganti

Publications (2)12.66 Total impact

• Article: A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.

  Dean A Heathcote, Hetal Patel, Sebastian H B Kroll, Pascale Hazel, Manikandan Periyasamy, Mary Alikian, Seshu K Kanneganti, Ashutosh S Jogalekar, Bodo Scheiper, Marion Barbazanges, [......], Alekasandra Siwicka, Robert D M Pace, Matthew J Fuchter, James P Snyder, Dennis C Liotta, Paul S Freemont, Eric O Aboagye, R Charles Coombes, Anthony G M Barrett, Simak Ali
  [show abstract] [hide abstract]
  ABSTRACT: Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
  Journal of Medicinal Chemistry 11/2010; 53(24):8508-22. · 4.80 Impact Factor
• Article: The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.

  Simak Ali, Dean A Heathcote, Sebastian H B Kroll, Ashutosh S Jogalekar, Bodo Scheiper, Hetal Patel, Jan Brackow, Alekasandra Siwicka, Matthew J Fuchter, Manikandan Periyasamy, Robert S Tolhurst, Seshu K Kanneganti, James P Snyder, Dennis C Liotta, Eric O Aboagye, Anthony G M Barrett, R Charles Coombes
  [show abstract] [hide abstract]
  ABSTRACT: Normal progression through the cell cycle requires the sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4, and CDK6. Direct or indirect deregulation of CDK activity is a feature of almost all cancers and has led to the development of CDK inhibitors as anticancer agents. The CDK-activating kinase (CAK) plays a critical role in regulating cell cycle by mediating the activating phosphorylation of CDK1, CDK2, CDK4, and CDK6. As such, CDK7, which also regulates transcription as part of the TFIIH basal transcription factor, is an attractive target for the development of anticancer drugs. Computer modeling of the CDK7 structure was used to design potential potent CDK7 inhibitors. Here, we show that a pyrazolo[1,5-a]pyrimidine-derived compound, BS-181, inhibited CAK activity with an IC(50) of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 micromol/L, with CDK2 being inhibited 35-fold less potently (IC(50) 880 nmol/L) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis to inhibit the growth of cancer cell lines, and showed antitumor effects in vivo. The drug was stable in vivo with a plasma elimination half-life in mice of 405 minutes after i.p. administration of 10 mg/kg. The same dose of drug inhibited the growth of MCF-7 human xenografts in nude mice. BS-181 therefore provides the first example of a potent and selective CDK7 inhibitor with potential as an anticancer agent.
  Cancer Research 09/2009; 69(15):6208-15. · 7.86 Impact Factor