TACH101: A First-in-Class KDM4-Targeted Therapy

 

A Critical Driver of Tumorigenesis and Novel Target for Cancer Therapy

TACH101 is a first-in-class, orally available, selective, and potent small-molecule inhibitor of the entire KDM4 protein family. This epigenetic regulator, comprising KDM4A, B, C, and D histone demethylases, drives tumorigenic pathways such as gene overexpression, genomic instability, uncontrolled cell proliferation, inhibition of apoptosis, and metastasis.

Discovered using our proprietary single-cell genomic analysis technology, TACH101 has demonstrated significant preclinical activity by effectively blocking the proliferation of multiple cancer cell lines and patient-derived organoid models, which are 3D tissue cultures derived from cancer stem cells that KDM4 also helps maintain for self-renewal.

In animal xenograft models across various cancer types, including colorectal, esophageal, breast, and lymphoma, TACH101 treatment reduced tumor growth by up to 100% and, importantly, reduced the number of tumor-initiating cancer stem cells responsible for relapses, metastases, and chemotherapy resistance.

KDM4 overexpression is associated with these and other cancer types, like prostate, making it an important novel therapeutic target. TACH101 (formerly QC8222) is currently in a first-in-human Phase 1 clinical trial (NCT05076552) for the treatment of advanced or metastatic cancers, making it the only KDM4 inhibitor in development.

KDM4 Publications

Chandhasin C, Dang V, Perabo F, Del Rosario J, Chen YK, Filvaroff E, Stafford JA, Clarke M. TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase. Anticancer Drugs. 2023 Nov 1;34(10):1122-1131. 

Perabo F, Chandhasin C, Yoo S, Dang V, Del Rosario JR, Chen YK, Stafford JA, Quake SR, Clarke MF. TACH101, a first-in-class pan-inhibitor of KDM4 for treatment of gastrointestinal cancers. J Clin Oncol. 2022. Vol 40, Issue 4 suppl 132 (Feb 1, 2022) 132-132.

Perabo F, Yoo S, Chandhasin C, Del Rosario JR, Chen YK, Filvaroff E, Stafford JA, Quake SR, Clarke MF. Identification of pharmacodynamic and sensitivity biomarkers for TACH101, a pan-inhibitor of KDM4 histone lysine demethylase. Mol Cancer Ther. 2021. Vol 20, suppl 12 (Dec 1, 2021) P086.

Perabo F, Yoo S, Chandhasin C, Del Rosario JR, Chen YK, Filvaroff E, Stafford JA, Quake SR, Clarke MF. TACH101, a first-in-class KDM4 inhibitor for treatment of triple-negative breast cancer. Ann Oncol. 2021. Vol 32, suppl 5 (Sep 1, 2021) S450-S451.

Chandhasin C, Yoo S, Del Rosario J, Chen YK, Stafford JA, Quake SR, Perabo F, Clarke MF. Inhibition of Histone Lysine Demethylases with TACH101, a First-in-Class Pan-Inhibitor of KDM4. J Clin Oncol. 2021. Vol 39, no. 15_suppl (May 20, 2021) 3105-3105.

Yoo S, Chandhasin C, Del Rosario J, Chen YK, Stafford JA, Quake SR, Perabo F, Clarke MF. Pharmacologic characterization of TACH101, a first-in-class KDM4 inhibitor for development as a cancer therapeutic. J Clin Oncol. 2021. Vol 39, no. 15_suppl (May 20, 2021) e15067.

Yoo S, Chandhasin C, Del Rosario J, Chen YK, Stafford JA, Quake SR, Perabo F, Clarke MF. TACH101, a first-in-class pan inhibitor of KDM4 histone lysine demethylases. Cancer Res. 2021. Volume 81, Issue 13 Supplement, pp. 2128.

Metzger E, Stepputtis SS, Strietz J, Preca BT, Urban S, Willmann D, Allen A, Zenk F, Iovino N, Bronsert P, Proske A, Follo M, Boerries M, Stickeler E, Xu J, Wallace MB, Stafford JA, Kanouni T, Maurer J, Schüle R. KDM4 Inhibition Targets Breast Cancer Stem-like Cells. Cancer Res. 2017 Nov 1;77(21):5900-5912.

Chen YK, Bonaldi T, Cuomo A, Del Rosario JR, Hosfield DJ, Kanouni T, Kao SC, Lai C, Lobo NA, Matuszkiewicz J, McGeehan A, O’Connell SM, Shi L, Stafford JA, Stansfield RK, Veal JM, Weiss MS, Yuen NY, Wallace MB. Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models. ACS Med Chem Lett. 2017 Jul 27;8(8):869-874.

Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017 Apr;16(4):241-263.

Awwad SW, Ayoub N. Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway. Biol Open. 2015 Mar 13;4(4):498-504.

Wu AR, Neff NF, Kalisky T, Dalerba P, Treutlein B, Rothenberg ME, Mburu FM, Mantalas GL, Sim S, Clarke MF, Quake SR. Quantitative assessment of single-cell RNA-sequencing methods. Comparative Study Nat Methods. 2014 Jan;11(1):41-6.

Labbé RM, Holowatyj A, Yang ZQ. Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. Am J Transl Res. 2013 Dec 1;6(1):1-15.

Berry WL, Janknecht R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 2013 May 15;73(10):2936-42.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11.