CDK12 Inhibitor

CDK12/13-IN-3 (Compound 12b) is the orally active inhibitor for CDK that inhibits CDK12 and CDK13 with IC₅₀ of 107.4 nM and 79.4 nM. CDK12/13-IN-3 inhibits the phosphorylation of Ser2 on the CTD of RNA polymerase II, induces DNA damage, and downregulates the gene expression of DNA damage response (DDR). CDK12/13-IN-3 exhibits antiproliferative activity against multiple cancer cells with IC₅₀ of nanomolar levels. CDK12/13-IN-3 exhibits antitumor effect in mouse models, exhibits good pharmacokinetic properties with an oral bioavailability of 53.6%.

PPA-037 is an orally active, highly potent and selective inhibitor of cyclin-dependent kinase 12 (CDK12). PPA-037 induces the degradation of cyclin K (Cyclin K), enhancing antiproliferative effects on tumor cells. PPA-037 is promising for research of cancers.

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.

CDK12-IN-8 (Compound Cpd143) is an orally active and highly selective inhibitor of cyclin-dependent kinase 12 (CDK12). CDK12-IN-8 inhibits CDK12-mediated phosphorylation of the C-terminal domain (CTD) serine 2 of RNA polymerase II, interfering with gene transcription elongation and DNA damage repair pathways. CDK12-IN-8 is promising for research of cancers with high CDK12 expression such as small cell lung cancer and triple-negative breast cancer.

PARP1/CDK12-IN-1 (107) is a dual inhibitor of CDK12 and PARP1, with IC₅₀ values of 285 nM and 34 nM for CDK12 and PARP1, respectively.

CDK12/13-IN-2 (Compound 24) is a covalent inhibitor of CDK12/13, with IC₅₀ values of 15.5 nM and 12.2 nM for CDK12 and CDK13, respectively. CDK12/13-IN-2 can inhibit the proliferation of breast cancer cells and can be used in the research of triple-negative breast cancer.

CDK7-IN-20 is a potent, selective and irreversible CDK7 (CDK) inhibitor with an IC₅₀ value of 4 nM. CDK7-IN-20 displays >206-fold selectivity for CDK7 over CDK1, CDK2, CDK3, CDK5, CDK6, CDK9 and CDK12 . CDK7-IN-20 has the potential for autosomal dominant polycystic kidney disease (ADPKD) research.

SY-5102 is a potent, selective, and orally active cyclin-dependent kinase (CDK7) inhibitor with a K_d value of 0.03 nM. SY-5102 occupies the ATP-binding pocket of CDK7 via non-covalent binding to inhibit CDK7 activity, and downregulates its phosphorylation of cyclin CDK and RNA polymerase II. SY-5102 inhibits cancer cell proliferation, and induces tumor growth inhibition and regression. SY-5102 can be used in research related to triple-negative breast cancer.

CDK12-IN-7 (Compound 2) is a CDK12 and CDK2 inhibitor with IC₅₀ values ​​of 42 and 196 nM, respectively. CDK12-IN-7 has anti-cell proliferation activity and can be used in cancer research.

CDK12-IN-4, a pyrazolotriazine, is a potent CDK12 inhibitor with an IC₅₀ of 0.641 μM at high ATP (2 mM). CDK12-IN-4 has no effect on CDK2/Cyclin E (IC₅₀>20 μM) and CDK9/Cyclin T1 (IC₅₀>20 μM) at high ATP (2 mM) (WO2021116178A1).

CDK12-IN-9 is a potent and selective CDK12 inhibitor with an IC₅₀ of 2.2 nM. CDK12-IN-9 inhibits pSER2 (a downstream marker of CDK12/13 activity). CDK12-IN-9 can be used for the research of cancer.

SR-5037 is an orally active CDK12 (IC₅₀ = 31 nM)/CDK13 inhibitor and CycK (DC₅₀ = 30 nM; D_max > 98%) molecular glue degrader. SR-5037 inhibits the enzymatic activity of CDK12/CycK and CDK13/CycK complexes. SR-5037 promotes the recruitment of DDB1 to the CDK12/CycK complex, thereby triggering proteasome-mediated CycK degradation. SR-5037 degrades active CycK in mouse models of triple-negative breast cancer. SR-5037 can be used in the research of cancers such as triple-negative breast cancer.

CDK-IN-9 (compound 24) is a potent CDK inhibitor, also as a molecular glue inducing an interaction between CDK12 and DDB1, with an IC₅₀ values of 4 nM for CDK2/E. CDK-IN-9 leads to polyubiquitination of cyclin K and its subsequent degradation. CDK-IN-9 induce apoptosis through dephosphorylation of retinoblastoma protein and RNA polymerase II.

CDK2-IN-42 (Compound H63) is a CDK12 inhibitor with an IC₅₀ value of 10 nM. CDK2-IN-42 has anti-ESCC (Esophageal Squamous Cell Carcinoma) cell activity. It can block transcriptional elongation, downregulate the core genes in the G1 phase to induce cell cycle arrest, and alter the CDK12-ATM/ATR-CHEK1/CHEK2 signaling axis, resulting in DNA damage. CDK2-IN-42 can effectively inhibit tumor growth in a xenograft mouse model of human ESCC KYSE150. CDK2-IN-42 holds great promise for research in the field of cancer.

HS-36 is a highly selective and orally active dual inhibitor of CDK4 and CDK9 with IC₅₀ values of 18.9 and 4.2 nM respectively. HS-36 exhibits nanomolar-level potent activity against various cancer cells, inducing G0/G1 phase arrest and promoting cell apoptosis. HS-36 efficiently inhibits tumor growth in a mouse model of MV-4-11 tumors. HS-36 can be used for the study of acute myeloid leukemia.

YJZ5118 is a selective CDK12/CDK13 inhibitor with IC₅₀ values of 39.5 nM and 26.4 nM. YJZ5118 suppresses transcription of DNA damage response genes and induces DNA damage in tumor cells. YJZ5118 inhibits proliferation and triggers apoptosis. YJZ5118 inhibits RNA polymerase II Ser2 phosphorylation and increases Akt pathway activity. YJZ5118 exhibits synergistic effects with Akt inhibitors. YJZ5118 can be used for the research of cancer, such as prostate cancer.

Hsp90-IN-42 is a heat shock protein 90 (Hsp90) inhibitor with an IC₅₀ of 15.65 nM against human targets. Hsp90-IN-42 destabilizes EGFR and inhibits the activation of the EGFR-Akt signaling pathway. Hsp90-IN-42 suppresses the proliferation and migration of cancer cells, induces cell cycle arrest by downregulating CDK12 and CDK13, and triggers mild apoptosis via downregulating Bcl-2 and upregulating Bax. Hsp90-IN-42 inhibits tumor growth in xenograft mouse models. Hsp90-IN-42 can be used in research related to colorectal cancer.

CDK12-Cyclin K ligand-1 is a ligand of PROTAC degrader that binds to the E3 ligase. CDK12-Cyclin K ligand-1 can be used in the synthesis of PROTAC degrader such as PP-C8 (HY-144691).