Tambiciclib (GFH009, JSH-009) dimaleate is an orally active, highly potent and selective CDK9 inhibitor ( IC50 = 1 nM), demonstrating >200-fold selectivity over other CDKs, >100-fold selectivity over DYRK1A / B, and excellent selectivity over 468 kinases/mutants. Tambiciclib dimaleate demonstrates potent in vitro and in vivo antileukemic efficacy in acute myeloid leukemia (AML) mouse models by inhibiting RNA Pol II phosphorylation, downregulating MCL1 and MYC, and inducing apoptosis. Tambiciclib dimaleate can be used for AML research [1].
In Vivo, Tambiciclib dimaleate (10 and 20 mg/kg, P.O., daily for 3 weeks) inhibits tumor growth and exerts no obvious toxicity in the MV4-11 cell-inoculated xenograft mouse model[1]. Tambiciclib dimaleate (10 and 15 mg/kg, P.O., daily until endpoint) dose-dependently prolongs overall survival in the MV4-11 cell-derived engraftment mouse model[1]. Tambiciclib dimaleate (10 and 20 mg/kg, P.O., daily for approximately 2 weeks) displays dose-dependent efficacy against antitumor progression in an AML patient-derived xenograft (PDX) mouse model[1].
In Vitro, Tambiciclib (JSH009) dimaleate (72 h) potently inhibits the growth of diverse AML cell lines and patient-derived primary cells (GI50 < 50 nM), but is far less potent against normal peripheral blood mononuclear cells (PBMCs) (GI50 > 10 μM), supporting a favorable safety profile[1]. Tambiciclib dimaleate (0.03-3 μM, 2 h) potently and dose-dependently inhibits the phosphorylation of RNA Pol II at Ser2 (EC50 < 300 nM) in OCI-AML-3, MV4-11, and HL-60 cells, while showing no effect on the CDK7-mediated phosphorylation of RNA Pol II at Ser5 or CDK9 at Thr186, confirming its high selectivity over CDK7[1]. Tambiciclib dimaleate (0.03-0.1 μM, 10 h) downregulates MCL1 and MYC expression at the transcriptional level alongside a broader reduction in overall transcription in MV4-11 cells[1]. Tambiciclib dimaleate (0.01-0.1 μM, 24 h) induces apoptosis in OCI-AML-3, MV4-11, and HL-60 cell lines, as evidenced by the cleavage of caspase-3 and PARP[1]. Tambiciclib dimaleate (0.01-0.05 μM, 24 h) has no effect on the cell cycle distribution of MV4-11 and OCI-AML-3 cells, consistent with the lack of significant changes in the expression of key cell cycle regulators (E2F1, Cyclin D1, CDC2) in MV4-11 cells[1].
References:
[1]. Wang L, et al. Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models. Invest New Drugs. 2020 Oct;38(5):1272-1281.
In Vivo, Tambiciclib dimaleate (10 and 20 mg/kg, P.O., daily for 3 weeks) inhibits tumor growth and exerts no obvious toxicity in the MV4-11 cell-inoculated xenograft mouse model[1]. Tambiciclib dimaleate (10 and 15 mg/kg, P.O., daily until endpoint) dose-dependently prolongs overall survival in the MV4-11 cell-derived engraftment mouse model[1]. Tambiciclib dimaleate (10 and 20 mg/kg, P.O., daily for approximately 2 weeks) displays dose-dependent efficacy against antitumor progression in an AML patient-derived xenograft (PDX) mouse model[1].
In Vitro, Tambiciclib (JSH009) dimaleate (72 h) potently inhibits the growth of diverse AML cell lines and patient-derived primary cells (GI50 < 50 nM), but is far less potent against normal peripheral blood mononuclear cells (PBMCs) (GI50 > 10 μM), supporting a favorable safety profile[1]. Tambiciclib dimaleate (0.03-3 μM, 2 h) potently and dose-dependently inhibits the phosphorylation of RNA Pol II at Ser2 (EC50 < 300 nM) in OCI-AML-3, MV4-11, and HL-60 cells, while showing no effect on the CDK7-mediated phosphorylation of RNA Pol II at Ser5 or CDK9 at Thr186, confirming its high selectivity over CDK7[1]. Tambiciclib dimaleate (0.03-0.1 μM, 10 h) downregulates MCL1 and MYC expression at the transcriptional level alongside a broader reduction in overall transcription in MV4-11 cells[1]. Tambiciclib dimaleate (0.01-0.1 μM, 24 h) induces apoptosis in OCI-AML-3, MV4-11, and HL-60 cell lines, as evidenced by the cleavage of caspase-3 and PARP[1]. Tambiciclib dimaleate (0.01-0.05 μM, 24 h) has no effect on the cell cycle distribution of MV4-11 and OCI-AML-3 cells, consistent with the lack of significant changes in the expression of key cell cycle regulators (E2F1, Cyclin D1, CDC2) in MV4-11 cells[1].
References:
[1]. Wang L, et al. Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models. Invest New Drugs. 2020 Oct;38(5):1272-1281.