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NAtURe BioteChNology | VOL 38 | AuguST 2020 | 905–916 | www.nature.com/naturebiotechnology EZH2 drug resistance in lymphoma is also a puzzle. Later-stage tumors, under the pressure of therapy, may develop clones that can tolerate the loss of EZH2, says Melnick. As a result, Epizyme is now supporting an investigator-sponsored clinical trial to test Tazverik together with chemotherapy as frontline treatment for lymphoma. How to best combine EZH2 inhibitors with other drugs, however, is unknown. Several companies are combining with standard androgen signaling inhibitors in prostate cancer, in part based on the ability of EZH2 inhibitors to reverse resistance to antiandrogen drugs in cells. A series of recent papers have also implicated EZH2 mutation and overexpression in immune dysfunction, including impaired antigen presentation and skewing of the T cell response. That’s part of the rationale for a new trial at MD Anderson Cancer Center, combining the Daiichi Sankyo dual EZH1/EZH2 inhibitor valemetostat with the immune checkpoint blocker Yervoy (ipilimumab) in bladder, renal and prostate cancer. There is also room for improvement in the drugs themselves. Constellation Pharmaceuticals began EZH2 drug discovery back around 2009. “This was by far not a trivial undertaking, not for us and not for anyone in the field,” says CSO Patrick Trojer. Like other methyltransferases, EZH2 obtains the methyl group from the compound S-adenosylmethionine (SAM), and most EZH2 inhibitors block EZH2 by out-competing SAM for binding, thus preventing transfer of the methyl group to the histone substrate. These EZH2 inhibitors all contain the same core motif, which binds the SAM pocket and is critical for drug potency. But the core also impairs drug solubility. GlaxoSmithKline dropped its EZH2 inhibitor in 2017 after phase 1 due to short plasma half-life. Companies including Epizyme optimized their compounds with good results, but many continue to fashion new ones with better properties. Constellation recently scrapped phase 3 plans for its EZH2 inhibitor, instead prioritizing a second-generation compound with “best in class potential,” says Trojer, because it stays bound to its target for much longer time. The upshot of Tazverik’s lymphoma approval is that it should boost company and investor interest in epigenetics. But there are pitfalls. BET bromodomain inhibitors, which target ‘reader’ proteins that recognize histone marks, are a good example. There are specificity issues when targeting histone readers. “My impression of these compounds is that they are somewhat unselective and toxic to cells,” says Melnick. Single-agent clinical trial results overall have been disappointing. Overinterpretation of preclinical experiments using high drug concentrations may be one reason, says Trojer. Constellation’s BET bromodomain inhibitor program is moving forward because the company eventually found a tumor type, myelofibrosis, highly sensitive to the drug. But Constellation has now decided to advance only those agents Table 1 | Selected eZh2 inhibitors in clinical development