2. PROTAC Cell Cycle/DNA Damage Apoptosis PI3K/Akt/mTOR Epigenetics
  3. DNA/RNA Synthesis Molecular Glues CDK Apoptosis RAD51 ATM/ATR PARP
  4. LL-K12-18

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.

For research use only. We do not sell to patients.

LL-K12-18

LL-K12-18 Chemical Structure

CAS No. : 3081311-94-3

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10 mM * 1 mL in DMSO
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LL-K12-18 Related Antibodies

Top Publications Citing Use of Products

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RNASE L DNA Polymerases RNA Polymerases Helicases DNA Ligase

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CDK1 CDK2 CDK3 CDK4 CDK5 CDK6 CDK7 CDK8 CDK9 CDK11 CDK12 CDK13 CDK14 CDK16 CDK19 CDC CLK Pho85 CDK10 CDK15 CDK17 CDK18 CDK20 PITSLRE

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ATM ATR TRRAP

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PARP PARP1 PARP2 PARP3 PARP4 TNKS1/PARP5A TNKS2/PARP5B PARP7 PARP10 PARP14 PARP15 PARP12 PARP16

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Description

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[1][2].
IC50 & Target

RNA Polymerase

 

CDK12/Cyclin K

283.9 nM (IC50)

In Vitro

LL-K12-18 (multiple concentrations; 120 h) potently inhibits the proliferation of MDA-MB-231 and MDA-MB-468 human breast cancer cells with sub-nanomolar potency (EC50 0.37 nM for MDA-MB-231, 0.03 nM for MDA-MB-468)[1].
LL-K12-18 (0.2-500 nM; 0-6 h) potently and rapidly degrades cyclin K in MDA-MB-231 cells via a DDB1-mediated ubiquitin-proteasome system-dependent mechanism, with minimal impact on CDK12 levels (DC50 0.38 nM)[1].
LL-K12-18 (25-2000 nM; 2-6 h) selectively degrades cyclin K (and downstream CDK13) in MDA-MB-231 cells, and specifically inhibits CDK12-mediated phosphorylation of the RNA polymerase II CTD Ser2 residue[1].
LL-K12-18 (50 nM (DDR assay); 25-2000 nM (damage/apoptosis assay); 6-24 h) downregulates DNA damage response gene expression and induces DNA damage and apoptosis in MDA-MB-231 cells[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

LL-K12-18 Related Antibodies

Western Blot Analysis[1]

Cell Line: MDA-MB-231 human breast cancer cells
Concentration: 0.2-500 nM (DC50 determination); 50 nM (degradation kinetics); 125-2000 nM (cyclin K rescue assays with pre-treatment inhibitors); 20-100 nM (cyclin K rescue assays with DDB1 shRNA)
Incubation Time: 4 h (DC50 determination); 0-6 h (degradation kinetics); unspecified (cyclin K rescue assays)
Result: Degraded cyclin K with a DC50 of 0.38 nM, and almost completely degraded cyclin K at 10 nM within 4 h.
Nearly fully degraded cyclin K within 2 h at 50 nM, a faster rate than its precursor.
Induced cyclin K degradation that was rescued by pre-treatment with the proteasome inhibitor MG132, the NAE inhibitor MLN-4924, or knockdown of DDB1 via shRNA.
Had minimal effect on CDK12 protein levels at active concentrations.

Western Blot Analysis[1]

Cell Line: MDA-MB-231 human breast cancer cells
Concentration: 25-2000 nM (cyclin/CDK selectivity assay); 2 μM (cyclin/CDK selectivity and RNA POL II phosphorylation assays)
Incubation Time: 2 h (proteomics analysis); 6 h (cyclin/CDK selectivity and RNA POL II phosphorylation assays)
Result: Significantly and selectively decreased cyclin K protein levels within 2 h; also reduced CDK13 levels, but had minimal impact on other tested proteins.
Reduced only cyclin K protein levels substantially among all tested cyclins (A2, D1, E1, H, T1) and CDKs (1, 2, 4, 6, 7, 9, 12) after 6 h treatment with up to 2000 nM.
Reduced phosphorylation of Ser2 on the RNA polymerase II CTD, but had a weak effect on Ser5 phosphorylation.

Real Time qPCR[1]

Cell Line: MDA-MB-231 human breast cancer cells
Concentration: 50 nM (DDR gene expression assay); 25-2000 nM (DNA damage/apoptosis marker assay)
Incubation Time: 6 h (DDR gene expression assay); 24 h (DNA damage/apoptosis marker assay)
Result: Significantly reduced the mRNA levels of DDR genes (FANCI, FANCD2, RAD51, SMARCC2, ATM, ATR) in MDA-MB-231 cells, with greater inhibition than its precursor.
Reduced protein levels of ATM and RAD51, and increased levels of γ-H2AX (a DNA damage marker) and cleaved-PARP (an apoptosis marker) after 24 h treatment.
Molecular Weight

559.49

Formula

C25H32Cl2N10O
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

CCN1C=NC2=C1N=C(N(CC3)CCN3C(CN(CC)CC)=O)N=C2NCC4=NC5=CC(Cl)=C(C=C5N4)Cl
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 25 mg/mL (44.68 mM; ultrasonic and warming and heat to 60°C; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.7873 mL 8.9367 mL 17.8734 mL
5 mM 0.3575 mL 1.7873 mL 3.5747 mL
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* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.7873 mL 8.9367 mL 17.8734 mL 44.6836 mL
5 mM 0.3575 mL 1.7873 mL 3.5747 mL 8.9367 mL
10 mM 0.1787 mL 0.8937 mL 1.7873 mL 4.4684 mL
15 mM 0.1192 mL 0.5958 mL 1.1916 mL 2.9789 mL
20 mM 0.0894 mL 0.4468 mL 0.8937 mL 2.2342 mL
25 mM 0.0715 mL 0.3575 mL 0.7149 mL 1.7873 mL
30 mM 0.0596 mL 0.2979 mL 0.5958 mL 1.4895 mL
40 mM 0.0447 mL 0.2234 mL 0.4468 mL 1.1171 mL
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LL-K12-18 Related Classifications

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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

LL-K12-183081311-94-3DNA/RNA SynthesisMolecular GluesCDKApoptosisRAD51ATM/ATRPARPCyclin dependent kinaseAtaxia telangiectasia mutatedATM and RAD3 relatedpoly ADP ribose polymerasecyclin KRNA polymerase II C-terminal domain Ser2DDB1γ-H2AXCDK12breast cancer cellsubiquitin-proteasome systemATMtriple negative breast cancerInhibitorinhibitorinhibit

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