KDM4

A Novel Target for Cancer Therapy

KDM4 is a family of histone demethylases that govern gene control by removing methyl groups from histones, and thereby regulating the accessibility of DNA to transcription factors. This can influence which genes are turned on or off as well a their level of expression.

The KDM4 family consists of four main isoforms (KDM4 A, B, C, and D). Functional redundancy and cross-activity has been observed across the KDM4 isoforms, therefore, inhibition of one isoform has been shown to to be ineffective. Pan-inhibition targeting multiple or all KDM4 isoforms is required to fully suppress KDM4 function.

In cancers, KDM4 has been shown to regulate critical signaling pathways involved in tumorigenesis such as cell proliferation, cancer stem cell maintenance, evasion of apoptosis, deficiency in DNA repair, metastasis, and stimulation of certain hormones.

KDM4 has been associated with driving cancers, as well as their resistance pathways, and is linked to aggressive disease and poor clinical outcomes.

KDM4 has emerged as a well-recognized anti-cancer target and Tachyon’s TACH101 is the only KDM4 inhibitor that is currently in clinical development. TACH101 is a potent, selective, pan-inhibitor of KDM4 proteins and is currently in a Phase 1 clinical trial for the treatment of advanced or metastatic cancers.

KDM4 Publications

Chandhasin C, Dang V, Perabo F, Del Rosario JR, Chen YK, Filvaroff E, Stafford JA, Clarke MF. TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase. Anticancer Drugs. 2023 Mar 24.

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, Chandhasin C, Yoo S, Del Rosario J, Chen YK, Filvaroff E, Stafford JA, Quake S, Clarke MF. TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma [abstract]. Cancer Res 2022;82(12_Suppl):Abstract nr 3720.

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.