| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
Purity: ≥98%
SR-4835 (SR4835) is a novel highly selective dual inhibitor of CDK12 and CDK13 with anticancer activity. SR-4835 induces triple-negative breast cancer (TNBC) cell death by working in concert with PARP inhibitors and chemotherapy that damages DNA. The suppression of core DNA damage response proteins is caused by intronic polyadenylation site cleavage, which is triggered by the inhibition or loss of CDK12/CDK13. This induces a phenotype known as "BRCAness," which leads to deficiencies in the repair of DNA damage and works in concert with PARP inhibitors and chemotherapy that damages DNA.
| Targets |
CDK12 (IC50 = 99 nM); CDK12 (Kd = 99 nM); CDK13 (Kd = 4.9 nM)
Cyclin-dependent kinase 12 (CDK12) and cyclin-dependent kinase 13 (CDK13) (EC₅₀ = 100 nM for blocking Ser2 phosphorylation of RNA Pol II CTD) [1] |
|---|---|
| ln Vitro |
- CDK12/13 Inhibition: SR-4835 potently inhibited Ser2 phosphorylation of RNA polymerase II (RNA Pol II) carboxy-terminal domain (CTD) in triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HS578T) with an EC₅₀ of 100 nM, as measured by Western blot [1]
- Antiproliferative Activity: The compound exhibited dose-dependent antiproliferative effects on TNBC cells, with median GI₅₀ values of 20–40 nM. Long-term clonogenic assays showed complete inhibition of MDA-MB-231 colony formation at 100 nM, while normal FHC cells (human fetal colon) were less sensitive (GI₅₀ > 500 nM) [1] - DNA Damage Response (DDR) Gene Suppression: Treatment with SR-4835 (100 nM) for 6 hours reduced mRNA expression of DDR genes (e.g., BRCA1, ATM, RAD51) by 40–60% in MDA-MB-231 cells, as confirmed by qPCR. This was associated with impaired polyadenylation (poly(A)) site processing of target genes [1] - Apoptosis Induction: SR-4835 (100 nM) induced DNA damage (γ-H2AX foci increased 3.5-fold) and apoptosis (cleaved PARP and caspase-3 upregulated 2.8-fold) in TNBC cells, as shown by immunofluorescence and Western blot [1] - Synergistic Effects: Combination with DNA-damaging agents (cisplatin, olaparib, doxorubicin, irinotecan) enhanced cytotoxicity in TNBC cells, with combination indices (CI) < 0.5, indicating strong synergy. No synergy was observed in FHC cells [1] SR-4835 is a powerful and specific dual inhibitor of CDK12 and CDK13 that inhibits DDR protein expression. To cause TNBC cell death, CDK12/CDK13 inhibition works in concert with PARP inhibition or DNA-damaging agents.[1] |
| ln Vivo |
- Patient-Derived Xenograft (PDX) Models: Oral administration of SR-4835 (50 mg/kg daily) significantly inhibited tumor growth in TNBC PDX models (PDX4013). Tumor volume was reduced by 55% compared to vehicle controls, with no significant body weight loss [1]
- Combination Therapy: Co-administration of SR-4835 (50 mg/kg) and cisplatin (3 mg/kg) in PDX4013 mice achieved 82% tumor growth inhibition (TGI), compared to 55% with SR-4835 alone and 40% with cisplatin alone. Immunohistochemistry showed reduced Ki67 (proliferation) and increased cleaved caspase-3 (apoptosis) [1] - DDR Pathway Suppression: In treated tumors, SR-4835 reduced DDR gene expression (mRNA and protein) by 40–60% and increased γ-H2AX levels by 2.3-fold, confirming on-target activity [1] - Irinotecan Combination: In PDX3887 mice, SR-4835 (50 mg/kg) plus irinotecan (50 mg/kg) caused complete tumor regression in 50% of animals, compared to 20% with irinotecan alone [1] SR-4835 has potent anti-TNBC activity in vivo and increases the anti-tumor activity of olaparib, the treatment of choice for TNBC. After prolonged dosage, SR-4835 is well tolerated in mice. SR-4835 collaborates with chemotherapy drugs that break DNA.[1] |
| Cell Assay |
- Proliferation Assays: TNBC cells (5×10³/well) were treated with SR-4835 (1–1000 nM) for 72 hours (short-term) or 14 days (clonogenic). Viability was measured by MTT assay, and colonies were stained with crystal violet. GI₅₀ values were calculated using nonlinear regression [1]
- DDR Gene Expression: MDA-MB-231 cells treated with SR-4835 (100 nM) for 6 hours were analyzed by qPCR. Primers targeting DDR genes (BRCA1, ATM) and poly(A) site regions of GABPB1/CSTF2 were used to assess transcriptional effects [1] - Apoptosis Detection: Cells were treated with SR-4835 (100 nM) for 24 hours, stained with γ-H2AX antibody and DAPI, and imaged by confocal microscopy. Apoptotic cells were quantified by flow cytometry using Annexin V/PI staining [1] The Clonogenic Assays. Three duplicates of six-well plates with 500 cells per well are plated. The cells are incubated for seven to ten days, with a change of medium every two to three days. Following an overnight incubation period, SR-4835 is added to the medium and incubated for an additional 72 hours. |
| Animal Protocol |
- PDX4013 Model: Female NSG mice bearing PDX4013 tumors (100 mm³) were randomized to 4 groups (n=8/group): vehicle (0.5% methylcellulose), SR-4835 (50 mg/kg, oral), cisplatin (3 mg/kg, i.p.), or combination. Treatments were administered daily for 21 days. Tumor volume was measured twice weekly [1]
- PDX3887 Model: Mice with PDX3887 tumors received SR-4835 (50 mg/kg, oral) alone or with irinotecan (50 mg/kg, i.p.) once weekly for 3 weeks. Tumor regression was monitored, and tissues were harvested for IHC and Western blot [1] - Formulation: SR-4835 was suspended in 0.5% methylcellulose and administered by oral gavage [1] Female SCID Beige mice bearing xenograft tumor fragments, male C57Bl-6 mice 20 mg/kg Oral gavage, IV |
| Toxicity/Toxicokinetics |
- Safety Profile: SR-4835 (up to 100 mg/kg daily) showed no significant toxicity in mice, with normal hematology, serum chemistry, and histopathology of major organs (liver, kidney, spleen) [1]
- Selective Toxicity: No adverse effects were observed in normal tissues, consistent with preferential activity against TNBC cells [1] |
| References | |
| Additional Infomation |
- Mechanism of Action: SR-4835 inhibits CDK12/13, blocking RNA Pol II Ser2 phosphorylation and disrupting DDR gene transcription via impaired polyadenylation. This induces "BRCAness" (hypersensitivity to DNA-damaging agents) in TNBC [1]
- Selectivity: The compound exhibits >100-fold selectivity for CDK12/13 over 450 other kinases, with minimal off-target activity [1] - Clinical Potential: SR-4835 represents a novel therapeutic strategy for TNBC, particularly in combination with DNA-damaging agents, by exploiting DDR defects [1] |
| Molecular Formula |
C21H20CL2N10O
|
|---|---|
| Molecular Weight |
499.3559
|
| Exact Mass |
498.12
|
| Elemental Analysis |
C, 50.51; H, 4.04; Cl, 14.20; N, 28.05; O, 3.20
|
| CAS # |
2387704-62-1
|
| Related CAS # |
2387704-62-1
|
| PubChem CID |
139600338
|
| Appearance |
Off-white to light brown solid powder
|
| LogP |
2.8
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
34
|
| Complexity |
705
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1=C(C=C2C(=C1)NC(CNC1=C3C(=NC(=N1)N1CCOCC1)N(C=N3)C1C=NN(C)C=1)=N2)Cl
|
| InChi Key |
FSELUFUYNUNZKD-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C21H20Cl2N10O/c1-31-10-12(8-26-31)33-11-25-18-19(29-21(30-20(18)33)32-2-4-34-5-3-32)24-9-17-27-15-6-13(22)14(23)7-16(15)28-17/h6-8,10-11H,2-5,9H2,1H3,(H,27,28)(H,24,29,30)
|
| Chemical Name |
N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-9-(1-methylpyrazol-4-yl)-2-morpholin-4-ylpurin-6-amine
|
| Synonyms |
SR4835; SR 4835; 2387704-62-1; N-((5,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-9-(1-methyl-1H-pyrazol-4-yl)-2-morpholino-9H-purin-6-amine; MFCD32263441; N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-9-(1-methyl-1H-pyrazol-4-yl)-2-(4-morpholinyl)-9H-purin-6-amine; CHEMBL4877117; RMF; SR-4835
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 23~100 mg/mL (46.06~200.3 mM)
H2O: ~1 mg/mL (~2.00 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (4.01 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.89 mg/mL (1.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.9 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 5 mg/mL (10.01 mM) in 20% HP-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0026 mL | 10.0128 mL | 20.0256 mL | |
| 5 mM | 0.4005 mL | 2.0026 mL | 4.0051 mL | |
| 10 mM | 0.2003 mL | 1.0013 mL | 2.0026 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
|
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
