Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor

Biopharmaceutics and Drug Disposition

Volumn 35, Issue 4, 2014, Pages 237-252

  Basavapathruni, Aravind ^a   Olhava, Edward J ^a   Daigle, Scott R ^a   Therkelsen, Carly A ^a   Jin, Lei ^a   Boriack Sjodin, P Ann ^a   Allain, Christina J ^a   Klaus, Christine R ^a   Raimondi, Alejandra ^a   Scott, Margaret Porter ^a   Dovletoglou, Angelos ^a   Richon, Victoria M ^a,b   Pollock, Roy M ^a   Copeland, Robert A ^a   Moyer, Mikel P ^a   Chesworth, Richard ^a   Pearson, Paul G ^a   Waters, Nigel J ^a  

^a EPIZYME INC   (United States)

^b SANOFI   (United States)

Author keywords

in vitro in vivo extrapolation; metabolite identification; MLL rearranged leukemia; nonclinical pharmacokinetics

Indexed keywords

2 (6 AMINO 9H PURIN 9 YL) 5 [[[3 [2 (5 TERT BUTYL 1H BENZIMIDAZOL 2 YL)ETHYL]CYCLOBUTYL](ISOPROPYL)AMINO]METHYL]TETRAHYDROFURAN 3,4 DIOL; ANTINEOPLASTIC AGENT; DRUG METABOLITE; METHYLTRANSFERASE INHIBITOR; BENZIMIDAZOLE DERIVATIVE; DOT1L PROTEIN, MOUSE; DOT1L PROTEIN, RAT; EPZ-5676; HISTONE LYSINE METHYLTRANSFERASE; METHYLTRANSFERASE; PLASMA PROTEIN;

AEROBIC METABOLISM; ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; FEMALE; GLOMERULUS FILTRATION RATE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; KIDNEY CLEARANCE; LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MALE; MAXIMUM PLASMA CONCENTRATION; MDCK CELL LINE; MEAN RESIDENCE TIME; MOUSE; NONHUMAN; PLASMA PROTEIN BINDING; RAT; STEADY STATE; TANDEM MASS SPECTROMETRY; TIME TO MAXIMUM PLASMA CONCENTRATION; TOTAL BODY WATER; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; DOG; LIVER CELL; METABOLISM; PERMEABILITY; SPRAGUE DAWLEY RAT;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZIMIDAZOLES; BLOOD PROTEINS; DOGS; HEPATOCYTES; HISTONE-LYSINE N-METHYLTRANSFERASE; MADIN DARBY CANINE KIDNEY CELLS; MALE; METHYLTRANSFERASES; MICE; MICROSOMES, LIVER; PERMEABILITY; RATS, SPRAGUE-DAWLEY;

EID: 84899459437     PISSN: 01422782     EISSN: 1099081X     Source Type: Journal    
DOI: 10.1002/bdd.1889     Document Type: Article

References (24)

1. Portela A, Esteller M,. Epigenetic modifications and human disease. Nature Biotechnol 2010; 28: 1057-1068.
2. Tamai H, Inokuchi K,. 11q23/MLL acute leukemia: update of clinical aspects. J Clin Exp Hematopathol 2010; 50: 91-98.
3. Ayton PM, Chen EH, Cleary ML,. Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein. Mol Cell Biol 2004; 24: 10470-10478. (Pubitemid 39507883)
4. Milne TA, Briggs SD, Brock HW, et al,. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 2002; 10: 1107-1117. (Pubitemid 35453828)
5. Nakamura T, Mori T, Tada S, et al,. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 2002; 10: 1119-1128. (Pubitemid 35453829)
6. Slany RK, Lavau C, Cleary ML,. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol Cell Biol 1998; 18: 122-129. (Pubitemid 28021024)
7. Zeleznik-Le NJ, Harden AM, Rowley JD,. 11q23 translocations split the 'AT-hook' cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc Natl Acad Sci U S A 1994; 91: 10610-10614.
8. Biswas D, Milne TA, Basrur V, et al,. Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. Proc Natl Acad Sci U S A 2011; 108: 15751-15756, S/1-S/7.
9. Daigle SR, Olhava EJ, Therkelsen CA, et al,. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011; 20: 53-65.
10. Basavapathruni A, Jin L, Daigle SR, et al,. Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Design 2012; 80: 971-980.
11. Daigle SR, Olhava EJ, Therkelsen CA, et al,. Potent inhibition of DOT1L as treatment for MLL-fusion leukemia. Blood 2013; 122 (6): 1017-1025.
12. Pang KS, Rowland M,. Hepatic clearance of drugs. I. Theoretical considerations of a 'well-stirred' model and a 'parallel tube' model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J Pharmacokinet Biopharm 1977; 5: 625-653. (Pubitemid 8253670)
13. Obach RS,. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 1999; 27: 1350-1359.
14. Houston JB,. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994; 47: 1469-1479. (Pubitemid 24167255)
15. Barter ZE, Bayliss MK, Beaune PH, et al,. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab 2007; 8: 33-45. (Pubitemid 46043890)
16. Davies B, Morris T,. Physiological parameters in laboratory animals and humans. Pharm Res 1993; 10: 1093-1095. (Pubitemid 23211439)
17. Ring BJ, Chien JY, Adkison KK, et al,. PhRMA CPCDC Initiative on Predictive Models of Human Pharmacokinetics, Part 3: Comparative assessment of prediction methods of human clearance. J Pharm Sci 2011; 100: 4090-4110.
18. Hinderling PH,. Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharmacol Rev 1997; 49: 279-295. (Pubitemid 27414916)
19. Sahin S, Benet LZ,. The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms. Pharm Res 2008; 25: 2869-2877.
20. van de Waterbeemd H,. Physicochemical Approaches to Drug Absorption. In Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability, van de Waterbeemd H, Testa B, (eds). Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2009; 40: 71-99. doi: 10.1002/9783527623860. ch5.
21. Di L, Keefer C, Scott DO, et al,. Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design. Eur J Med Chem 2012; 57: 441-448.
22. Lam SP, Devinsky F, Gorrod JW,. Biological N-oxidation of adenine and 9-alkyl derivatives. Eur J Drug Metab Pharmacokinet 1987; 12: 239-243. (Pubitemid 18058704)
23. Deng L, Zhang L, Yao Y, et al,. Synthesis, activity and metabolic stability of non-ribose containing inhibitors of histone methyltransferase DOT1L. Med Chem Comm 2013; 4: 822-826.
24. Anglin JL, Song Y,. A medicinal chemistry perspective for targeting histone H3 lysine79 methyltransferase DOT1L. J Med Chem 2013; 56 (22): 8972-8983.