CDKI-73 (LS-007) 是具有口服活性的、高效的CDK9抑制剂，其对CDK9、CDK1 和 CDK2 的Ki值分别为 4 nM、4 nM 和 3 nM。CDKI-73 可下调 RNA 聚合酶 II 的磷酸化。CDKI-73 也是一种 Rab11 的抑制剂。
| 生物活性 | CDKI-73 (LS-007) is an orally active and highly efficaciousCDK9inhibitor, withKivalues of 4 nM, 4 nM and 3 nM forCDK9,CDK1andCDK2, respectively. CDKI-73 down-regulates the RNAPII phosphorylation. CDKI-73 is also a novel pharmacological inhibitor of Rab11 cargo delivery and innate immune secretion[1][2][3][4].
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| IC50& Target | CDK2 3.27 nM (IC50) | CDK9 5.78 nM (IC50) | CDK1 8.17 nM (IC50) | CDK4 8.18 nM (IC50) | CDK6 37.68 nM (IC50) | CDK7 134.26 nM (IC50) | CDK1 4 nM (Ki) | CDK2 3 nM (Ki) | CDK9 4 nM (Ki) | CDK7 91 nM (Ki) |
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体外研究
(In Vitro) | CDKI-73 is highly cytotoxic to primary leukemia cells derived from CLL patients (mean LD50= 0.08 μM) and shows>500-fold selectivity for primary leukemia cells over normal B-lymphocytes (LD50= 40.5 μM)[1].
CDKI-73 (0.1 μM, 4 h) inhibits the phosphorylation of serine 2 of RNA polymerase II and MCL1 protein expression in CLL cells[1].
CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II[1].
CDKI-73 is highly effective against all cell lines tested with an IC50in the range of 0.012-0.517 μM; in particular three MLL-AML cell lines, namely MOLM13, MV4-11 and THP-1, were highly sensitive to CDKI-73 with IC50values<0.062 μM[3].
Cell Viability Assay[1]. | Cell Line: | CLL cells. | | Concentration: | 0-1 μM. | | Incubation Time: | 48 h. | | Result: | Shows preferential cytotoxicity in CLL cells. |
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体内研究
(In Vivo) | CDKI-73 (25, 50, 100 mg/kg) markedly decreases tumor growth in a dose-dependent manner and results in a prolongation of animal life span (P< 0.001) without causing body weight loss and other overt toxicities.[3].
| Animal Model: | MV4-11 tumor bearing mice[3]. | | Dosage: | 25 mg/kg. | | Administration: | Orally once everyday for 33 days. | | Result: | Caused a remarkable delay in tumor growth compared to vehicle-treated mice, as reflected in a percentage for the mean tumor volume in treated to control mice of 43% at day 31. |
| Animal Model: | Balb/C mice aged 6-8 weeks[3]. | | Dosage: | 2 mg/kg (IV), 10, 20 and 40 mg/kg (PO). (Pharmacokinetic Analysis.) | | Administration: | IV and PO, single dose. | | Result: | The Cmaxincreased from 1.29 to 3.66 μM at a mean time of 1 h and the area under the curve (AUC) of CDKI-73 increased from 3.51 to 12.8 μM.h when the oral dose was escalated from 10 to 40 mg/kg.
CDKI-73 was eliminated from plasma with a mean terminal half-life (T1/2) of 2 h. Its oral
bioavailability (F) ranged from 54 to 85% across the three doses.
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | 4°C, stored under nitrogen *In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen) |
| 溶解性数据 | In Vitro: DMSO : ≥ 52 mg/mL(131.83 mM) *"≥" means soluble, but saturation unknown. 配制储备液 | 1 mM | 2.5352 mL | 12.6759 mL | 25.3518 mL | | 5 mM | 0.5070 mL | 2.5352 mL | 5.0704 mL | | 10 mM | 0.2535 mL | 1.2676 mL | 2.5352 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month (stored under nitrogen)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.67 mg/mL (6.77 mM); Clear solution
此方案可获得 ≥ 2.67 mg/mL (6.77 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 26.7 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 *以上所有助溶剂都可在本网站选购。
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