CDK Inhibitor

Butyrolactone I is an orally active and ATP-competitive inhibitor of CDK1. Butyrolactone I inhibits NF-κB, cdc2 kinase, Bax, ROS production, modulates the PERK/CHOP. Butyrolactone I mitigates heat-stress-induced Apoptosis. Butyrolactone I shows anti-inflammatory and intestinal protective activity. Butyrolactone I has antitumor effects against non-small cell lung, small cell lung, prostate cancer and leukemia. Butyrolactone I can be used in NASH research.

Ribociclib-d₆ (LEE011-d₆) hydrochloride is a deuterium labeled Ribociclib. Ribociclib is a highly specific CDK4/6 inhibitor with IC₅₀ values of 10 nM and 39 nM, respectively, and is over 1,000-fold less potent against the cyclin B/CDK1 complex.

CDDD11-8 is an orally active, potent and selective inhibitor of CDK9 and FLT3-ITD, with K_i values of 8 and 13 nM, respectively. CDDD11-8 reduces the proliferation of leukemia cell lines and was particularly effective against those harboring FLT3-ITD mutation.

NU6027 is a potent and ATP-competitive inhibitor of both CDK1 and CDK2, with K_is of 2.5 μM and 1.3 μM, respectively. NU6027 is also a potent inhibitor of ATR and enhances hydroxyurea and cisplatin cytotoxicity in an ATR-dependent manner.

CGP-74514 (Compound 13) is a highly selective cyclin-dependent kinase 1 (CDK1) inhibitor (IC₅₀=25 nM). CGP-74514 inhibits CDK1/cyclin B complex activity, arrests the cell cycle at G₂/M phase and induces tumor cell apoptosis. CGP-74514 is promising for research of bladder cancer.

ZNL-05-044 is a CDK11 inhibitor with an IC₅₀s of 0.23 μM and 0.27 μM against CDK11A and CDK11B, respectively (NanoBRET assay). ZNL-05-044 leads to G2/M cell cycle arrest and impairs RNA splicing.

CDK12-IN-6, a pyrazolotriazine, is a potent CDK12 inhibitor with an IC₅₀ of 1.19 μM at high ATP (2 mM). CDK12-IN-6 has no effect on CDK2/Cyclin E (IC₅₀>20 μM) and CDK9/Cyclin T1 (IC₅₀>20 μM) at high ATP (2 mM) (WO2021116178A1).

(-)-Syringaresinol is an orally active isomer of syringaresinol (HY-N8307) found in Annona Montana. (-)-Syringaresinol exhibits antioxidant, anti-inflammatory, and anticancer activities. (-)-Syringaresinol can alleviate ulcerative colitis via the PI3K-Akt/MAPK/Wnt signaling pathway. (-)-Syringaresinol inhibits HL-60 cell proliferation by arresting the G1 phase and inducing apoptosis. (-)-Syringaresinol inhibits LPS (HY-D1056)-induced microglial activation by downregulating the NF-κB p65 signaling pathway and its interaction with ERβ, exerting anti-neuroinflammatory effects.

CDK4/6-IN-15 is an orally active and selective CDK4/6 inhibitor. CDK4/6-IN-15 potently inhibits cancer cells growth. CDK4/6-IN-15 arrests cell cycle at G1 phase and suppresses retinoblastoma tumour suppressor protein (Rb) phosphorylation at S780 and E2 factor (E2F)-regulated gene expression.

CCT036477 is a Wnt/β-catenin pathway inhibitor. CCT036477 blocks transcription at β-catenin without altering its levels. CCT036477 inhibits proliferation of various cancer cells, development of embryos, and expression of Wnt target genes (PPARδ, Cyclin D1, TCF4, and ID2).

CLK1-IN-3 (compound 10ad) is a potent and selective Clk1 inhibitor, with an IC₅₀ of 5 nM and over 300-fold selectivity for Dyrk1A. CLK1-IN-3 also shows a relatively potent inhibition against Clk2 and Clk4, with IC₅₀ values of 42 and 108 nM, respectively. CLK1-IN-3 potently induces autophagy in vitro. CLK1-IN-3 can be used for acute liver injury (ALI) research.

TMX-2039 is a pan-CDK inhibitor for both cell cycle CDKs (CDK1, CDK2, CDK4, CDK5 and CDK6) and transcriptional CDKs (CDK7 and CDK9), with IC₅₀s of 2.6, 1.0, 52.1, 0.5, 35.0, 32.5 and 25 nM, respectively. TMX-2039 acts as a Ligands for Target Protein for PROTACs.

LY3177833 (Example 4) is an orally active CDC7 and pMCM2 inhibitor with IC₅₀ values of 3.3 nM and 290 nM, respectively. LY3177833 is a senescence inducer.

TG693 is an orally active inhibitor of CLK1. TG693 regulates the mutated exon 31 of the dystrophin gene in vivo. TG693 is used in Duchenne muscular dystrophy (DMD) research.

Zeltociclib is a cyclin-dependent kinase inhibitor with antitumor effects.

RRibociclib (LEE011) succinate hydrate is an ATP-competitive and orally active CDK4/6 inhibitor that crosses the blood-brain barrier with IC₅₀ values of 10 nM and 39 nM, respectively, and is over 1,000-fold less potent against the cyclin B/CDK1 complex.

M2N12 is a potent and highly selective cell division cycle 25C protein phosphatase (Cdc25C) inhibitor with an IC₅₀ value of 0.09  μM. M2N12 also has promising activity against Cdc25A and Cdc25B with IC₅₀ values of  0.53  μM and 1.39 μM, respectively. M2N12 has anti-tumor activity and can be used for cancer research.

DK419 is a potent and orally active Wnt/β-catenin signaling inhibitor, with an IC₅₀ of 0.19 μM. DK419 reduces protein lelvels of Axin2, β-catenin, c-Myc, Cyclin D1 and Survivin and induces production of pAMPK.

Vevorisertib (ARQ 751) is an orally active allosteric AKT inhibitor that blocks AKT phosphorylation. Vevorisertib inhibits tumor cell proliferation through Cyclin D1 and Ki67. Vevorisertib inhibits liver fibrosis through collagen accumulation, alpha-SMA, COL1, and TGF-beta. Vevorisertib reduces total bilirubin. Vevorisertib significantly reduces tumor size in a cirrhotic rat HCC model. Vevorisertib can be used for research on hepatocellular carcinoma.

Cdc7-IN-1 (Compound 13) is a highly potent, selective and ATP competitive inhibitor of Cdc7 kinase, with an IC₅₀ value of 0.6 nM at 1 mM ATP and with slow off-rate characteristics. Cdc7-IN-1 potently inhibits Cdc7 activity in cancer cells, and effectively induces cell death.