Preclinical Metabolism and Pharmacokinetics of SB1317 (TG02), a Potent CDK/JAK2/FLT3 Inhibitor

Mohammed Khalid Pasha, Ramesh Jayaraman, Venkatesh Pilla Reddy, Pauline Yeo, Evelyn Goh, Anthony Williams, Kee Chuan Goh, Ethirajulu Kantharaj

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14 Citations (Scopus)


SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed >99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution (>0.6 L/kg), oral bioavailability of 24%, ~ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate. © 2012 Bentham Science Publishers.
Original languageEnglish
Pages (from-to)33-42
Number of pages10
JournalDrug Metabolism Letters
Issue number1
Publication statusPublished - 17-Apr-2012


  • ADME
  • CYP450
  • Metabolism
  • Pharmacokinetics
  • SB1317/TG02
  • cytochrome P450 1A
  • cytochrome P450 2C19
  • cytochrome P450 2C9
  • cytochrome P450 2D6
  • cytochrome P450 3A4
  • sulotroban
  • animal cell
  • animal experiment
  • area under the curve
  • article
  • CACO 2 cell line
  • chemical structure
  • controlled study
  • drug absorption
  • drug binding
  • drug bioavailability
  • drug clearance
  • drug distribution
  • drug half life
  • drug metabolism
  • drug penetration
  • drug solubility
  • drug stability
  • drug tissue level
  • female
  • human
  • human cell
  • IC50
  • in vitro study
  • liver cell
  • liver microsome
  • male
  • maximum plasma concentration
  • mouse
  • nonhuman
  • phenotype
  • plasma protein binding
  • priority journal
  • time to maximum plasma concentration
  • tissue distribution

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