CDK9 Inhibitor

Casein Kinase inhibitor A86 is a potent and orally active casein kinase 1α (CK1α) inhibitor. Casein Kinase inhibitor A86 also inhibits of CDK7 (TFIIH) and CDK9 (P-TEFb). Casein Kinase inhibitor A861 induces leukemia cell apoptosis, and has potent anti-leukemic activities.

NVP-LCQ195 (LCQ-195) is an inhibitor of CDK1/2/3/5/9. NVP-LCQ195 induces cell cycle arrest and eventual apoptotic cell death of multiple myeloma (MM) cells. NVP-LCQ195 triggers decreased amplitude of transcriptional signatures related to oncogenesis, drug resistance and stem cell renewal in MM cell lines.

AT7519 (AT7519M) TFA as a potent inhibitor of CDKs, with IC₅₀s of 210, 47, 100, 13, 170, and <10 nM for CDK1, CDK2, CDK4 to CDK6, and CDK9, respectively.

CDK9/EZH2-IN-1 (Compound D16) is a CDK9/EZH2 dual-target inhibitor (IC₅₀: 83.9/108.6 nM). CDK9/EZH2-IN-1 induces apoptosis and DNA double-strand breaks (DSBs). CDK9/EZH2-IN-1 inhibits the proliferation activity of MKN45, MDA-MB-453 and SW620 cancer cells (IC₅₀ values are 136.3, 171.3 and 315.7 nM, respectively).

CDK12-IN-5, a pyrazolotriazine, is a potent CDK12 inhibitor with an IC₅₀ of 23.9 nM at high ATP (2 mM). CDK12-IN-5 has no effect on CDK2/Cyclin E (IC₅₀=173 μM) and CDK9/Cyclin T1 (IC₅₀=127 μM) at high ATP (2 mM) (WO2021116178A1).

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.

CK7, a Cdk2/9 inhibitor, can be used for the synthesis of Nek1 inhibitor BSc5231 and BSc5367.

YX0798 is a selective and orally active CDK9 inhibitor (K_d: 0.28 nM). YX0798 downregulates the oncoprotein c-MYC and pro-survival protein MCL-1. YX0798 disrupts the cell cycle and results in transcriptomic reprogramming, eventually leading to cell apoptosis. YX0798 has antitumor activity.

CDK9-IN-12 displays the optimal CDK9 inhibitory activity with an IC₅₀ value of 5.41 nM.

BS-181 is a potent and selective CDK7 inhibitor (IC₅₀=21 nM) than Seliciclib (HY-30237). BS-181 is also against CDK2, CDK5 and CDK9 with IC₅₀ values of 880, 3000 and 4200 nM, respectively (fails to block CDK1, 4 and 6). BS-181 inhibits a panel of cancer cells growth (IC₅₀=11.5 μM-37.3 μM) and induces cell apoptosis. BS-181 has the potential for the research of cancer therapy.

Bohemine is a purine analogue and is a synthetic and selective CDK inhibitor with IC₅₀s of 4.6 μM, 83 μM, and 2.7 μM for Cdk2/cyclin E, Cdk2/cyclin A, and Cdk9/cyclin T1, respectively. Bohemine also inhibits ERK2 with an IC₅₀ of 52 μM and has less inhibitory effect on CDK1, CDK4 and CDK6. Bohemine has a broad spectrum anti-cancer activities.

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.

CDK9-IN-10 is a potent CDK9 inhibitor. CDK9-IN-10 is the ligand for the PROTAC CDK9 degrader-2 (HY-112811).

CDK9-IN-14 is a potent and selective CDK9 inhibitor with IC₅₀ of 6.92 nM. CDK9-IN-14 has a relatively strong inhibitory effect on MV4;11 cells and in vivo tumor models, and has a good selectivity and a low toxicity and few side effects.

GW297361 is an oxindole CDK inhibitor that elicits a Pho85-selective response in cells. GW297361 inhibits yeast Cdk1 and Pho85 with IC₅₀s of 20 nM and 400 nM in vitro, respectively.

Olomoucine II is a potent CDK inhibitor with IC₅₀ values of 0.06, 0.1, 0.45, 7.6, 19.8 µM for CDK9/cyclin T, CDK2/cyclin E, CDK7/cyclin H, CDK1/cyclin B, CDK4/cyclin D1, respectively. Olomoucine II shows antiproliferative activity.

ZLMT-12 (compound 35), tacrine derivatives, is a potent, orally active CDK2/9 inhibitor with IC₅₀ values of 0.002 and 0.011 μM for CDK9 and CDK2, respectively. ZLMT-12 has a weak inhibitory effect on AChE (IC₅₀=19.023 μM) and BChE (IC₅₀=2.768 μM). ZLMT-12 has low toxicity and antiproliferative activity. ZLMT-12 induces apoptosis and arrests the cell cycle in the S phase and G2/M phase.

BS-181 dihydrochloride is a potent and selective CDK7 inhibitor (IC₅₀=21 nM) than Seliciclib (HY-30237). BS-181 is also against CDK2, CDK5 and CDK9 with IC₅₀ values of 880 nM, 3000 nM and 4200 nM, respectively (fails to block CDK1, 4 and 6). BS-181 dihydrochloride inhibits a panel of cancer cells growth (IC₅₀=11.5 μM-37.3 μM) and induces cell apoptosis. BS-181 dihydrochloride has the potential for the research of cancer therapy.

CDK9-IN-9 (example 2) is a potent and selective CDK9 inhibitor with an IC₅₀ of 1.8 nM. CDK9-IN-9 inhibits CDK2 with an IC₅₀ of 155 nM. CDK9-IN-9 has anti-cancer activity.

Riviciclib (P276-00 free base) is a potent cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK9-cyclinT1, CDK4-cyclin D1, and CDK1-cyclinB with IC₅₀s of 20 nM, 63 nM, and 79 nM, respectively. Riviciclib shows antitumor activity on cisplatin-resistant cells.