CDKI-73 (LS-007) 是一种具有口服活性且高效的 CDK9 抑制剂，对 CDK9、CDK1 和 CDK2 的 Ki 值分别为 4 nM、4 nM 和 3 nM。
CDKI-73 is a potent CDK9 inhibitor with Ki of 4 nM; shows selective toxicity to CLL cells(LD50=80 nM) versus normal B cell and normal CD34+ cell(LD50>20 uM).IC50 value: 4 nM/80 nM(Ki/LD50) [1]Target: CDK9 inhibitorin vitro: CDKI-73 was cytotoxic to all of the CLL samples tested (n = 38) with a mean LD50 value of 0.08uM ± 0.10 uM following exposure to drug for 48h. In contrast, normal B-lymphocytes (n = 10) and CD34+ normal bone marrow cells (n = 5) were significantly less susceptible to the cytotoxic effects of CDKI-73. Treatment of CLL cells with 0.1 uM CDKI-73 for 4h inhibited the phosphorylation of cdk9 and ser2 of RNA polymerase II. CDKI-73 induces a rapid loss of MCL1 protein and this is mediated by significant inhibition at the level of gene transcription. However, this inhibition is not restricted to MCL1 as similar reductions in XIAP and CCND2 were also observed following exposure to CDKI-73 for 4h [1]. CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis [2]. in vivo: CDKI-73 exhibited a favorable pharmacokinetic profile with oral bioavailability of F = 56% following a single intravenous bolus dose at 2 mg/kg and an oral dose at 10 mg/kg in mice [1].
参考文献:
[1]. Xie S, et al. Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells. Acta Pharmacol Sin. 2016 Nov;37(11):1481-1489.
[2]. Lam F, et al. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget. 2014 Sep 15;5(17):7691-704.
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