title: Formation and anti-tumor activity of uncommon in vitro and in vivo metabolites of CPI-613, a novel anti-tumor compound that selectively alters tumor energy metabolism.
abstract: CPI-613 is a novel anti-tumor compound with a mechanism-of-action which appears distinct from the current classes of anti-cancer agents used in the clinic. CPI-613 demonstrates both in vitro and in vivo anti-tumor activity. In vitro metabolic studies using liver S9 were performed which demonstrated that CPI-613 undergoes both phase 1 (oxidation) and phase 2 (glucuronidation) transformations. Its metabolic half-life varied between species and ranged from 8 minutes (Hanford minipig) to 47 minutes (CD-1 mouse). We performed metabolite mass assessments using selected in vitro incubation samples and demonstrated that +16 amu oxidation with and without +176 amu glucuronidation products were generated by human and animal liver S9. LC/MS/MS fragmentation patterns showed that an uncommon sulfoxide metabolite was formed and the O-glucuronidation occurred at the terminal carboxyl moiety. We observed that the +192 amu sulfoxide/glucuronide was generated only in human liver S9 and not by any of the other species tested. Synthetic metabolites were prepared and compared with the enzymatically-generated metabolites. Both the chromatographic retention times and the LC/MS/MS fragmentation patterns were similar, demonstrating that the synthetic metabolites were virtually identical to the S9-generated products. CYP450 reaction phenotyping and inhibition data both suggested that multiple CYP isozymes (2C8 and 3A4, along with minor contributions by 2C9 and 2C19) were involved in CPI-613 metabolism and sulfoxide formation. Plasma samples from human subjects dosed with CPI-613 also contained the sulfoxide ± glucuronide metabolites. These results show that the in vitro- and in vivo-generated phase 1 and phase 2 metabolites were in good agreement.
authors: Cornerstone Pharmaceuticals, Inc., 1 Duncan Drive, Cranbury, NJ 08512, USA. king@cornerstonepharma.com
authors: King C
authors: KC
authors: Lee
authors: Robert
authors: R
authors: Shorr
authors: Robert
authors: R
authors: Rodriguez
authors: Claudia
authors: C
authors: Maturo
authors: Lakmal W
authors: LW
authors: Boteju
authors: Adrian
authors: A
authors: Sheldon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002210:Caprylates / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013454:Sulfoxides / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; D020719:Glucuronides; D013440:Sulfides; D013454:Sulfoxides; C568850:devimistat