THZ1

• CAT Number: I013889
• CAS Number: 1604810-83-4
• Molecular Formula: C₃₁H₂₈ClN₇O₂
• Molecular Weight: 566.05
• Purity: 95%
• Target: CDK7
• Solubility: DMSO: ≥ 27 mg/mL
• IUPAC Name: N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(E)-4-(dimethylamino)but-2-enoyl]amino]benzamide
• InChI: InChI=1S/C31H28ClN7O2/c1-39(2)16-6-11-28(40)35-21-14-12-20(13-15-21)30(41)36-22-7-5-8-23(17-22)37-31-34-19-26(32)29(38-31)25-18-33-27-10-4-3-9-24(25)27/h3-15,17-19,33H,16H2,1-2H3,(H,35,40)(H,36,41)(H,34,37,38)/b11-6+
• InChIKey: OBJNFLYHUXWUPF-IZZDOVSWSA-N
• SMILES: CN(C)CC=CC(=O)NC1=CC=C(C=C1)C(=O)NC2=CC=CC(=C2)NC3=NC=C(C(=N3)C4=CNC5=CC=CC=C54)Cl

THZ1(CAT: I013889) is a small-molecule inhibitor of cyclin-dependent kinase 7 (CDK7), a protein kinase that plays a critical role in the regulation of transcription by RNA polymerase II. By inhibiting CDK7, THZ1 can block the expression of certain genes that are required for the survival and proliferation of cancer cells. THZ1 has shown promising results in preclinical studies, particularly in the treatment of various types of solid tumors and hematological malignancies. It has been found to be effective in inducing apoptosis and cell cycle arrest in cancer cells, as well as sensitizing them to other types of therapies, such as radiation therapy and chemotherapy. THZ1 is currently undergoing clinical trials to evaluate its safety and efficacy in humans.

Reference

1. Cancer Lett. 2019 Dec 5. pii: S0304-3835(19)30611-1. doi: 10.1016/j.canlet.2019.12.005. [Epub ahead of print]
The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma.
Chow PM(1), Liu SH(2), Chang YW(3), Kuo KL(4), Lin WC(5), Huang KH(6).
Author information:
(1)Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: . (2)Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipe, 100, Taiwan. Electronic address: . (3)Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: . (4)Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: . (5)Department of Pathology, National Taiwan University Hospital, Taipe, 100, Taiwan. Electronic address: . (6)Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address: .
Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC. However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.

2. Cell Death Dis. 2019 Aug 9;10(8):602. doi: 10.1038/s41419-019-1831-7.
CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263.
Huang T(1), Ding X(1), Xu G(1), Chen G(2), Cao Y(1), Peng C(1), Shen S(1), Lv Y(1), Wang L(3), Zou X(4).
Author information:
(1)Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. (2)Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. (3)Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. . (4)Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. .
Cholangiocarcinoma (CCA) is a fatal disease without effective targeted therapy. We screened a small-molecule library of 116 inhibitors targeting different targets of the cell cycle and discovered several kinases, including Cyclin-dependent kinase 7 (CDK7) as vulnerabilities in CCA. Analysis of multiple CCA data sets demonstrated that CDK7 was overexpressed in CCA tissues. Further studies demonstrated that CDK7 inhibitor THZ1 inhibited cell viability and induced apoptosis in CCA cells. We also showed that THZ1 inhibited CCA cell growth in a xenograft model. RNA-sequencing followed by Gene ontology analysis showed a striking impact of THZ1 on DNA-templated transcriptional programs. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition. A number of oncogenic transcription factors and survival proteins, like MCL1, FOSL1, and RUNX1, were repressed by THZ1. MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment. Accordingly, combining THZ1 with a BCL2/BCL-XL inhibitor ABT-263 synergized in impairing cell growth and driving apoptosis. Our results demonstrate CDK7 as a potential target in treating CCA. Combinations of CDK7 inhibition and BCL2/BCL-XL inhibition may offer a novel therapeutic strategy for CCA.

3. J Cancer. 2019 Jun 9;10(16):3778-3788. doi: 10.7150/jca.30359. eCollection 2019.
Anti-tumor Drug THZ1 Suppresses TGFβ2-mediated EMT in Lens Epithelial Cells via Notch and TGFβ/Smad Signaling Pathway.
Ning J(1), Ma X(1), Long C(1), Mao Y(1), Kuang X(1)(2), Huang Z(1), Fan Y(1), Zhang H(1), Xia Q(1), Wang R(3), Liang Y(4), Lin S(4), Zhang Q(1), Shen H(1)(2).
Author information:
(1)State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China. (2)Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China. (3)The Second Clinical Medicine School of Lanzhou University, No.199, West Donggang Road, Lanzhou, Gansu Province, 730000, China. (4)Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Selective covalent CDK7 inhibitor THZ1 is a promising potential anti-tumor drug in many kinds of cancers. Epithelial-mesenchymal Transition (EMT) is highly related to cancer initiation, development, invasion and metastasis and other pathogenesis processes. We treated cancer cell line Hela229 and three retinoblastoma cell lines so-RB50, WERI-Rb-1, Y79 with gradient concentration of THZ1, and found that THZ1 could inhibit cell viability and EMT, suggesting that THZ1 may be a promising drug for human cervical cancer and retinoblastoma treatment. Our results verified the role of THZ1 in EMT for the first time, however, the mechanism needs further study. Here we report that THZ1 suppresses the TGFβ2 induced EMT in human SRA01/04 lens epithelial cells (LECs), rabbit primary lens epithelial cells, and whole rat lens culture semi-in vivo model. RNA-sequencing and KEGG analysis revealed that the THZ1 inhibits EMT by down-regulating phosphorylate Smad2 and Notch signaling pathway. On the other hand, we found that THZ1 could strongly inhibit LECs proliferation through G2/M phase arrest as well as attenuating of MAPK, PI3K/AKT signaling pathway. Our results uncovered the function and underlying mechanism of THZ1 in regulation of EMT, which provides a new perspective of the anti-tumor effect by THZ1 and may offer a novel treatment for PCO.