CDK2 Inhibitor

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.

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.

(E/Z)-BIO-acetoxime (GSK-3 Inhibitor X) is a potent and selective GSK-3α/β inhibitor, with an IC₅₀ of 10 nM. (E/Z)-BIO-acetoxime shows more than 200-flod selectivity over CDK5/p25, CDK2/cyclin A and CDK1/cyclin B (IC₅₀=2.4, 4.3, 63 μM).

CDK2-IN-40 is a CDK2 (Cyclin dependent kinase 2) inhibitor, extracted from patent WO 2024/254245 A1 (Example 1). CDK2-IN-40 inhibits CDK2/Cyclin E1 with an IC₅₀ of ≤ 10 nM.

GSK-3 inhibitor 4 is an orally active and brain-penetrant inhibitor of GSK-3, CDK2, and CDK5, with IC₅₀ values of 0.56 nM (GSK-3β), 0.45 nM (GSK-3α), 0.47 μM, and 0.68 μM, respectively. GSK-3 inhibitor 4 effectively reduces the phosphorylation level of Tau protein. GSK-3 inhibitor 4 can be used in Alzheimer's disease (AD) studies.

XYD049 is a CRBN-based molecular glue degrader targeting GSPT1, with a DC₅₀ of 19 nM. XYD049 mediates the formation of a ternary complex between CRBN and GSPT1, thereby triggering CRBN- and proteasome-dependent degradation of GSPT1. By degrading GSPT1, XYD049 downregulates castration-resistant prostate cancer (CRPC)-related oncogenes, including BCL2, CDK2, E2F3, EGFR, HSP90B1, TMPRSS2, AR, AR-V7, PSA and c-Myc. XYD049 inhibits cancer cell growth and suppresses tumor growth in mice. XYD049 can be used for research on castration-resistant prostate cancer. XYD049 consists of a linker (black part) NH2-C5-NH-Boc (HY-W004710), a CRBN-based E3 ligase ligand (blue part) Thalidomide 4-fluoride (HY-41547), and a target protein ligand (red part) GSPT1 ligand-1 (HY-170821), among which the E3 ligase ligand plus linker forms the conjugate E3 Ligase Ligand-linker Conjugate 158 (HY-170822).

GDC-4198 (RGT-419B) is an orally active CDK4/2 inhibitor with desired degrees of selectivity against kinases such as CDK6, CDK9 and GSK3β. GDC-4198 inhibits the activity of cyclin-CDK complexes, blocks phosphorylation of the retinoblastoma protein (pRb), arresting the cell cycle transition from G1 to S phase. GDC-4198 is promising for research of cancers, such as breast cancer (especially hormone receptor-positive, HER2-negative type), lung cancer, and colorectal cancer.

IV-361 is an orally active and selective CDK7 inhibitor (K_i≤50 nM). IV-361 has anti-cancer activity (US20190256531A1).

PT-262 is a potent ROCK inhibitor with an IC₅₀ value of around 5 μM. PT-262 induces the loss of mitochondrial membrane potential and elevates the caspase-3 activation and apoptosis. PT-262 inhibits the ERK and CDC2 phosphorylation via a p53-independent pathway. PT-262 blocks cytoskeleton function and cell migration. PT-262 has anti-cancer activity.

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.

Multi-target kinase inhibitor 2 is a multi-targeted kinase inhibitor, and exhibits activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC₅₀ values of 79 nM, 40 nM,136 nM, and 204 nM, respectively. Multi-target kinase inhibitor 2 shows cytotoxic effects were observed against HepG2, HeLa , MDA-MB-231 and MCF-7, with IC₅₀ of 41, 57, 51 and 59 μM. Multi-target kinase inhibitor 2 induces cell cycle arrest and apoptosis in HepG2 cells.

Akt1&PKA-IN-1 is a potent dual Akt/PKA inhibitor with IC₅₀ values of 0.03 , 0.11 μM, and 9.8 μM for PKAa, Akt, and CDK2, respectively. Akt1&PKA-IN-1 is selective for cyclin-dependent kinase 2 (CDK2).

RGB-286147 is a selective and ATP-competitive CDK and CDK-related kinases (CRK) inhibitor with IC₅₀ values ranging from 9-839 nM. RGB-286147 shows less active against other non-CDK/CRK kinases. RGB-286147 induces cell apoptosis, and exhibits anti-tumor activity.

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.

AMG 925 HCl is a potent, selective, and orally available FLT3/CDK4 dual inhibitor with IC₅₀s of 2±1 nM and 3±1 nM, respectively.

Akt1&PKA-IN-2 (Compound R-29) is a AKT1 and PKA inhibitor with selectivity for CDK2, with IC₅₀ values of 0.007 and 0.01 μM, respectively. Akt1&PKA-IN-2 is applicable for cancer research.

PNU112455A hydrochloride is an ATP-competitive CDK2 and CDK5 inhibitor. PNU112455A hydrochloride binds to the ATP site of CDK2 and CDK5 with K_ms of 3.6 and 3.2 μM, respectively.

CDK7-IN-28 (CDK7-1276) is a potent CDK7 inhibitor(IC₅₀＜5 nM). CDK7-IN-28 can inhibit proliferation of MDA-MB-468 cell line by blocking cell cycle and inhibiting DNA replication.