title: Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor.
abstract: 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.
authors.affiliation: S*BIO Pte Ltd, 1 Science Park Road, No. 05-09, The Capricorn, Singapore Science Park II, Singapore.
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Venkatesh Pilla
authors.initials: VP
authors.lastname: Reddy
authors.forename: Pauline
authors.initials: P
authors.lastname: Yeo
authors.forename: Evelyn
authors.initials: E
authors.lastname: Goh
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Ethirajulu
authors.initials: E
authors.lastname: Kantharaj
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014018:Tissue Distribution; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
chemical_list: C570909:14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D003577:Cytochrome P-450 Enzyme System; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; D018844:Cyclin-Dependent Kinases