EPZ-719

Among all published SETD2 inhibitors, EPZ-719 represents the best probe, based on available data. Other potent SETD2 inhibitors include sinefungin analogs (Zheng et al., JACS 2012, 134, 18004−18014) and EMZ0414, which was also published by a group at Epizyme (Alford et al., ACS Med. Chem. Lett. 2022, 13, 1137−1143). The sinefungin analogs are less potent then EPZ-719 and somewhat less selective within the protein family. No profiling data outside the protein family have been reported for these compounds; likewise, neither cellular nor in vivo data are available. EMZ0414 is a compound that is currently undergoing Phase I clinical studies. It exhibits comparable potency as EPZ-719, has a better PK, and in vivo antitumor activity has been demonstrated for the compound. However, as far as I can see no selectivity data have been published for the EMZ0414, neither within the protein family nor otherwise. At this point, however, important control data are still missing for EPZ-719. No data are available for an adequate control and/or orthogonal probe in the proliferation assay. Proliferation data are reported only for EPZ-719 and a cIosely related compound of similar biochemical activity. In principle, cpd. 25 from the paper could serve as orthogonal probe. No data are available for a quantitative correlation between target engagement and antiproliferative effects. In this context, it is interesting to note that ref. 20 in the paper reads: "SETD2 target engagement for 32 [= EPZ-719] and related compounds was confirmed via a direct correlation between the reduction of H3K36me3 levels and in vitro cellular antiproliferative effects. These data were presented by Totman et al. at EHA 2021 (HemaSphere 2021, 5:S2, 44) and will be detailed in a SETD2 biology-focused manuscript in preparation." No such paper can be found in the literature and the EHA abstract just refers to "a" SETD2 inhibitor without spelling out the code number for this compound. While the relevant data seem to have been generated, they are not published. In addition, data against an SETD2-independent multiple myeloma cell lines should be obtained. The KMS-11 and KMS-34 cell lines both contain the t(4;14)(p16;q32) chromosomal translocation, which appears to make these cells dependent on SETD2. Thus, EPZ-719 should not be active against multiple myeloma cells that do not contain these aberrations and is should also not be active against other types of cancer cell lines. There really is no specific dose recommendation for efficacy experiments in animals and no such experiments are reported in the paper that describes the probe. All in vivo data are PK data, from which a recommended dose could be derived in principle. In fact, the paper says that at oral doses of 30 and 100 mg/kg the time above the cellular biochemical IC50 is 6 and 12 h, respectively. If this suffices for a relevant pharmacological effect would have to be proven. Apart from this, the bioavailability reported here for a 30 mg/kg dose is confusing (I cannot see the BAV for the 100 mg/kg dose). Based on the values given above, the AUC-based oral BAV of the compound at 30 mg/kg should be around 8.5%, which is low. However, the AUC of 803 does not match the one given in the SI of the paper, which is 2681 (803 is the SD for this mean values!) which makes the BAV ca. 28% and this also what is reported in the SI for the paper. A BAV of 28% is not unreasonable for a probe, but it is unclear what the 70% BAV given above means. For the 100 mg/kg dose the SI of the paper reports an oral BAV of 63% which is good. But all the data are based on only three mice per dose, which is the bare minimum.