CDK12 Inhibitor

THZ1 is a selective and potent covalent CDK7 inhibitor with an IC₅₀ of 3.2 nM. THZ1 also inhibits the closely related kinases CDK12 and CDK13 and downregulates MYC expression.

THZ531 is a selective and covalent inhibitor of both CDK12 and CDK13 with IC₅₀s of 158 nM and 69 nM, respectively.

SY-5609 (CDK7-IN-3) is an orally active, highly selective, noncovalent CDK7 inhibitor with a K_D of 0.065 nM. SY-5609 shows poor inhibition on CDK2 (K_i=2600 nM), CDK9 (K_i=960 nM), CDK12 (K_i=870 nM). SY-5609 induces apoptosis in tumor cells and has antitumor activity.

SR-4835 is a potent, highly selective and ATP competitive dual inhibitor of CDK12/CDK13 (CDK12: IC₅₀=99 nM, K_d=98 nM; CDK13: K_d=4.9 nM). SR-4835 acts in synergy with DNA-damaging chemotherapy and PARP inhibitors and provokes triple-negative breast cancer (TNBC) cell death.

BSJ-4-116 is a PROTAC connected by ligands for Cereblon and CDK. BSJ-4-116 is a highly potent and selective CDK12 degrader (PROTAC) with an IC₅₀ of 6 nM. BSJ-4-116 downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation). BSJ-4-116 exhibits potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor Olaparib (HY-10162).

GW780056X is a CDK12 inhibitor. GW780056X decreases nuclear foci count in DM1 cells. GW780056X can be used for the research of myotonic dystrophy type 1.

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.

THZ1 Hydrochloride is a selective and potent covalent CDK7 inhibitor with an IC₅₀ of 3.2 nM. THZ1 Hydrochloride also inhibits the closely related kinases CDK12 and CDK13 and downregulates MYC expression.

CDK12-IN-2 is a potent, selective and nanomolar CDK12 inhibitor (IC₅₀=52 nM) with good physicochemical properties. CDK12-IN-2 is also a strong CDK13 inhibitor due to CDK13 is the closest homologue of CDK12. CDK12-IN-2 shows excellent kinase selectivity for CDK12 over CDK2, 9, 8, and 7. CDK12-IN-2 inhibits the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II. CDK12-IN-2 can be used an excellent chemical probe for functional studies of CDK12.

MFH290 is an orally active, selective covalent CDK12/CDK13 inhibitor, with an IC₅₀ of 25 nM against human CDK12 and 49 nM against human CDK13. MFH290 reduces the phosphorylation level of CTD-RNAPII-Ser2, downregulates genes related to DNA damage response (DDR), and inhibits transcription factors regulated by super-enhancers. MFH290 can be used in research related to various cancers including leukemia.

LL-K12-18 is a CDK12 kinase inhibitor and a dual-site molecular glue. LL-K12-18 inhibits human CDK12 with an IC₅₀ value of 283.9 nM, and selectively degrades cyclin K via the ubiquitin-proteasome system by stabilizing the CDK12-DDB1 complex. LL-K12-18 downregulates DNA damage response genes, reduces the phosphorylation level of CTD Ser2 in RNA polymerase II, and modulates biomarkers such as ATM, RAD51, γ-H2AX and cleaved PARP, thereby effectively inducing apoptosis and inhibiting proliferation of breast cancer cells. LL-K12-18 exhibits high target selectivity and serves as a research tool for studies on triple-negative breast cancer.

CDK12-IN-3 is a potent and selective CDK12 inhibitor with an IC₅₀ of 491 nM in enzymatic assay.

BSJ-01-175 is a potent and selective CDK12/13 covalent inhibitor. BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells.

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).

CDK9-IN-13 (compound 38) is potent and selective CDK9 inhibitor, with an IC₅₀ of <3 nM. CDK9-IN-13 exhibits short half-lives in rodents.

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

CDK12-IN-E9 is a potent and selective covalent CDK12 inhibitor and a non-covalent CDK9 inhibitor, while avoiding ABC transporter-mediated efflux. CDK12-IN-E9 has weak binding ability to CDK7/CyclinH complex with an IC₅₀> 1 μM.

SHR5428 is a potent, orally active, selective and noncovalent inhibitor of CDK7 with highly potent CDK7 enzymatic activity (IC₅₀=2.3 nM). SHR5428 inhibits triple negative breast cancer cellular activity on MDA-MB-468 cell (IC₅₀=6.6 nM).

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).

PP-C8 is a potent and selective PROTAC CDK12-Cyclin K degrader. PP-C8 induces CDK12-Cyclin K degradation with DC₅₀s of 416 and 412 nM for CDK12 and Cyclin K, respectively. PP-C8 demonstrates profound synergistic antiproliferative effects with PARP inhibitor in triple-negative breast cancer (TNBC).