Background:

0.002 μM for biochemical IC50; 0.032 μM for cellular EC50.

CPI-1205 is an EZH2 inhibitor.

Polycomb repressive complex 2 (PRC2) plays a key role in transcriptional silencing partially by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function relates with certain malignancies and poor prognosis. EZH2 is thus representing a promising candidate oncology target for pharmacological intervention.

In vitro: Previous study reported that the treatment with CPI-1205 caused apoptosis in multiple myeloma and plasmacytoma cell models. CPI-1205 also had a clean selectivity profile when tested against 30 other histone or DNA methyltransferases. In addition, CPI-1205 demonstrated modest selectivity when tested against enhancer of zeste homologue 1 (EZH1) that is a methyltransferase highly related to EZH2 [1].

In vivo: In animal study, CPI-1205 was dosed at 160 mg/kg orally twice daily for 25 days in tumor bearing female CB-17 SCID mice. By the treatment of tumor-bearing mice with CPI-1205, tumor regression was observed within two weeks. By the end of day 25, significant tumor growth inhibition was recorded. CPI-1205 was found to be well-tolerated for repeat dosing as observed by the absence of significant body weight loss. In addition, analysis of plasma and tumor at 1 h post last dose on day 25 showed sufficient plasma and tumor tissue concentrations [1].

Clinical trial: A study to evaluate CPI-1205 in patients with B-cell lymphomas is currently recruiting participants [2].

参考文献:
[1] Vaswani RG et al.  Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas. J Med Chem. 2016 Nov 10;59(21):9928-9941.
[2] https://clinicaltrials. gov/ct2/show/NCT02395601 term=CPI-1205&rank=1.