MedKoo Cat#: 593163 | Name: SR-4835
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

SR-4835 is a highly selective dual inhibitor of CDK12 and CDK13, which disables triple-negative breast cancer (TNBC) cells. Mechanistically, inhibition or loss of CDK12/CDK13 triggers intronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins. This provokes a "BRCAness" phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors.

Chemical Structure

SR-4835
CAS#2387704-62-1

Theoretical Analysis

MedKoo Cat#: 593163

Name: SR-4835

CAS#: 2387704-62-1

Chemical Formula: C21H20Cl2N10O

Exact Mass: 498.1199

Molecular Weight: 499.36

Elemental Analysis: C, 50.51; H, 4.04; Cl, 14.20; N, 28.05; O, 3.20

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,850.00 Ready to ship
1g USD 4,250.00 Ready to ship
2g USD 6,950.00 Ready to ship
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Synonym
SR4835; SR 4835; SR-4835;
IUPAC/Chemical Name
9H-​Purin-​6-​amine, N-​[(5,​6-​dichloro-​1H-​benzimidazol-​2-​yl)​methyl]​-​9-​(1-​methyl-​1H-​pyrazol-​4-​yl)​-​2-​(4-​morpholinyl)​-
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)
SMILES Code
CN1N=CC(N2C3=NC(N4CCOCC4)=NC(NCC5=NC(C=C(Cl)C(Cl)=C6)=C6N5)=C3N=C2)=C1
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Biological target:
SR-4835 is a highly selective dual inhibitor of CDK12 and CDK13 with IC50 of 99 nM and Kd of 98 nM for CDK12 and IC50 of 4.9 nM for CDK13. SR-4835 disables triple-negative breast cancer (TNBC) cells.
In vitro activity:
SR-4835 acts as a molecular glue that recruits the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex to target cyclin K for degradation. SR-4835 uniquely promotes cyclin K degradation via the proteasome. SR-4835 promotes DDB1 interaction with the CDK12-cyclin K complex. Docking studies and structure-activity relationship analyses of SR-4835 revealed the importance of the benzimidazole side-chain in molecular glue activity. Reference: Cell Death Discov. 2023 Dec 16;9(1):459. https://pubmed.ncbi.nlm.nih.gov/38104154/
In vivo activity:
SR-4835's anti-tumor activity was assessed in a PDX model (PDX4013) derived from a triple-negative breast cancer (TNBC) patient with limited response to dasatinib and docetaxel treatment. Tumor growth markedly decreased in SR-4835-treated mice compared to controls. Endpoint studies revealed reduced expression of DDR genes and elevated levels of γ-H2AX protein. SR-4835 treatment did not induce weight loss. Additionally, SR-4835 significantly impaired tumor growth. Reference: Cancer Cell. 2019 Nov 11;36(5):545-558.e7. https://pubmed.ncbi.nlm.nih.gov/31668947/
Solvent mg/mL mM comments
Solubility
DMSO 5.0 10.00
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 499.36 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Houles T, Boucher J, Lavoie G, MacLeod G, Lin S, Angers S, Roux PP. The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. Cell Death Discov. 2023 Dec 16;9(1):459. doi: 10.1038/s41420-023-01754-x. PMID: 38104154; PMCID: PMC10725499. 2. Hopkins JL, Zou L. Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy. Cancer Cell. 2019 Nov 11;36(5):461-463. doi: 10.1016/j.ccell.2019.10.012. PMID: 31715127. 3. Li Y, Zhang H, Li Q, Zou P, Huang X, Wu C, Tan L. CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett. 2020 Dec 28;495:12-21. doi: 10.1016/j.canlet.2020.09.011. Epub 2020 Sep 15. PMID: 32941949. 4. Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer Cell. 2019 Nov 11;36(5):545-558.e7. doi: 10.1016/j.ccell.2019.09.004. Epub 2019 Oct 24. PMID: 31668947.
In vitro protocol:
1. Houles T, Boucher J, Lavoie G, MacLeod G, Lin S, Angers S, Roux PP. The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. Cell Death Discov. 2023 Dec 16;9(1):459. doi: 10.1038/s41420-023-01754-x. PMID: 38104154; PMCID: PMC10725499. 2. Hopkins JL, Zou L. Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy. Cancer Cell. 2019 Nov 11;36(5):461-463. doi: 10.1016/j.ccell.2019.10.012. PMID: 31715127.
In vivo protocol:
1. Li Y, Zhang H, Li Q, Zou P, Huang X, Wu C, Tan L. CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett. 2020 Dec 28;495:12-21. doi: 10.1016/j.canlet.2020.09.011. Epub 2020 Sep 15. PMID: 32941949. 2. Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer Cell. 2019 Nov 11;36(5):545-558.e7. doi: 10.1016/j.ccell.2019.09.004. Epub 2019 Oct 24. PMID: 31668947.
1: Ghosh P, Schmitz M, Pandurangan T, Zeleke ST, Chan SC, Mosior J, Sun L, Palve V, Grassie D, Anand K, Frydman S, Roush WR, Schönbrunn E, Geyer M, Duckett D, Monastyrskyi A. Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K. RSC Chem Biol. 2024 Oct 11. doi: 10.1039/d4cb00190g. Epub ahead of print. PMID: 39450271; PMCID: PMC11494886. 2: Zhang Z, Li Y, Yang J, Li J, Lin X, Liu T, Yang S, Lin J, Xue S, Yu J, Tang C, Li Z, Liu L, Ye Z, Deng Y, Li Z, Chen K, Ding H, Luo C, Lin H. Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex. Nat Commun. 2024 Aug 1;15(1):6477. doi: 10.1038/s41467-024-50642-0. PMID: 39090085; PMCID: PMC11294606. 3: Zhu T, Li Q, Zhang Z, Shi J, Li Y, Zhang F, Li L, Song X, Shen J, Jia R. ARID1A loss promotes RNA editing of CDK13 in an ADAR1-dependent manner. BMC Biol. 2024 Jun 5;22(1):132. doi: 10.1186/s12915-024-01927-9. PMID: 38835016; PMCID: PMC11151582. 4: Orhan E, Velazquez C, Tabet I, Fenou L, Rodier G, Orsetti B, Jacot W, Sardet C, Theillet C. CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer. Cancer Lett. 2024 May 1;589:216820. doi: 10.1016/j.canlet.2024.216820. Epub 2024 Apr 3. PMID: 38574883. 5: Houles T, Boucher J, Lavoie G, MacLeod G, Lin S, Angers S, Roux PP. The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma. Cell Death Discov. 2023 Dec 16;9(1):459. doi: 10.1038/s41420-023-01754-x. PMID: 38104154; PMCID: PMC10725499. 6: Schmitz M, Kaltheuner IH, Anand K, Düster R, Moecking J, Monastyrskyi A, Duckett DR, Roush WR, Geyer M. The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation. J Biol Chem. 2024 Jan;300(1):105501. doi: 10.1016/j.jbc.2023.105501. Epub 2023 Nov 26. PMID: 38016516; PMCID: PMC10767194. 7: Bai Y, Liu Z, Li Y, Zhao H, Lai C, Zhao S, Chen K, Luo C, Yang X, Wang F. Structural Mass Spectrometry Probes the Inhibitor-Induced Allosteric Activation of CDK12/CDK13-Cyclin K Dissociation. J Am Chem Soc. 2023 May 31;145(21):11477-11481. doi: 10.1021/jacs.3c01697. Epub 2023 May 19. PMID: 37207290. 8: Liu S, Wu J, Lu X, Guo C, Zheng Q, Wang Y, Hu Q, Bian S, Luo L, Cheng Q, Liu Z, Dai W. Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway. Exp Cell Res. 2023 Jul 1;428(1):113613. doi: 10.1016/j.yexcr.2023.113613. Epub 2023 Apr 24. PMID: 37100369. 9: Dai W, Wu J, Peng X, Hou W, Huang H, Cheng Q, Liu Z, Luyten W, Schoofs L, Zhou J, Liu S. CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer. Clin Transl Med. 2022 Oct;12(10):e1087. doi: 10.1002/ctm2.1087. PMID: 36254394; PMCID: PMC9577262. 10: Wu Z, Wang M, Li F, Wang F, Jia J, Feng Z, Huo X, Yang J, Jin W, Sa R, Gao W, Yu L. CDK13-Mediated Cell Cycle Disorder Promotes Tumorigenesis of High HMGA2 Expression Gastric Cancer. Front Mol Biosci. 2021 Aug 26;8:707295. doi: 10.3389/fmolb.2021.707295. PMID: 34513922; PMCID: PMC8427521. 11: Li Y, Zhang H, Li Q, Zou P, Huang X, Wu C, Tan L. CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett. 2020 Dec 28;495:12-21. doi: 10.1016/j.canlet.2020.09.011. Epub 2020 Sep 15. PMID: 32941949. 12: Hopkins JL, Zou L. Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy. Cancer Cell. 2019 Nov 11;36(5):461-463. doi: 10.1016/j.ccell.2019.10.012. PMID: 31715127. 13: Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer Cell. 2019 Nov 11;36(5):545-558.e7. doi: 10.1016/j.ccell.2019.09.004. Epub 2019 Oct 24. PMID: 31668947.