CDK6/PIM1-IN-1

CDK6/PIM1-IN-1 is a potent and balanced dual CDK6/PIM1 inhibitor with IC50 values of 39 and 88 nM, respectively. CDK6/PIM1-IN-1 inhibits CDK4 (IC50=3.6 nM). CDK6/PIM1-IN-1 significantly inhibits acute myeloid leukemia (AML) cell proliferation, arrest cell cycle at the G1 phase, and promote cell apoptosis. CDK6/PIM1-IN-1 exhibits potent anti-AML activity[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> Pim

Signaling Pathways >> Cell Cycle/DNA Damage >> CDK

CDK6/cyclinD1:39 nM (IC50)

PIM1:88 nM (IC50)

CDK1/cyclinB:>10 μM (IC50)

CDK2/cyclinA:2.274 μM (IC50)

CDK3/Cyclin E:>10 μM (IC50)

Cdk4/cyclin D1:3.6 nM (IC50)

Cdk5/p25:>10 μM (IC50)

CDK7/Cyclin H/MNAT1:393 nM (IC50)

CDK9/cyclinT1:440 nM (IC50)

CDK12/Cyclin K:>10 μM (IC50)

CDK13/Cyclin K:>10 μM (IC50)

PIM2:>10 μM (IC50)

PIM3:92 nM (IC50)

CDK6/PIM1-IN-1 (compound 51) exhibits more than 10 times selectivity over CDK1 (IC50>10 μM), CDK2 (IC50=2.274 μM), CDK3 (IC50>10 μM), CDK5 (IC50>10 μM), CDK7 (IC50=393 nM), CDK9 (IC50=440 nM), CDK12 (IC50>10 μM), and CDK13 (IC50>10 μM). CDK6/PIM1-IN-1 shows inhibitory activity against PIM2 (IC50>10 μM) and PIM3 (IC50=92 nM)[1]. CDK6/PIM1-IN-1 inhibits proliferation in AML cells (K562 cell,GI50=1.026 μM; HL-60 cell,GI50=1.069 μM; MOLM13 cell, GI50=1.362 μM)[1]. CDK6/PIM1-IN-1 (0.5, 1, 1.5 μM) causes a G1 arrest in a dose-dependent manner in K562 and HL-60 cell lines[1]. CDK6/PIM1-IN-1 (1, 2, 4 μM) promotes the apoptosis of K562 and HL-60 cell lines in a dose-dependent manner[1]. CDK6/PIM1-IN-1 (0.5, 1, 1.5 μM; for 24 h) reduces p-retinoblastoma (RB) and p-BAD levels in a concentration-dependent manner. CDK6/PIM1-IN-1 decreases the PIM1 level[1].

CDK6/PIM1-IN-1 (compound 51; orally; 60, 90 mg/kg/day; 17 days) displays more potent antitumor activity in BALB/c mice with K562 cell lines[1]. CDK6/PIM1-IN-1 (iv; 5 mg/kg) has the t1/2, MRT0-∞, and AUC0-∞ values of 9.78 h, 14.61 h, and 1153.74 h·ng/mL, respectively in Sprague–Dawley (SD) rats[1]. CDK6/PIM1-IN-1 (po; 5 mg/kg) has the t1/2, Tmax, Cmax, and AUC0-∞ of 15.81 h, 11 h, 152.31 ng/mL, and 5152.92 h·ng/mL, respectively in SD rats[1].

[1]. Kai Yuan, et al. Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia. J Med Chem. 2022 Jan 13;65(1):857-875.