Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies

Lampe, John W.; Alford, Joshua S.; Boriak-Sjodin, P. Ann; Brach, Dorothy; Cosmopoulos, Kat; Duncan, Kenneth W.; Eckley, Sean; Foley, Megan; Harvey, Darren M.; Motwani, Vinny; Munchhof, Michael J.; Raimondi, Alejandra; Riera, Thomas V.; Tang, Cuyue; Thomenius, Michael J.; Totman, Jennifer; Farrow, Neil A.

doi:10.1021/acsmedchemlett.1c00272

Cited by 20 publications

(17 citation statements)

References 18 publications

(21 reference statements)

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“…In our recent report on the discovery of the SETD2 inhibitor tool compound EPZ-719, we focused primarily on exploration of the structure–activity relationship (SAR) with respect to the indole motif and the central core of the molecule, leading to SETD2 inhibitor 2 and the closely related analogues 3 and 3-F (see Figure 1 ). 14 The unique binding mode of these aniline-containing inhibitors was also disclosed in that report. Anilines are prevalent in modern drug discovery screening libraries because of their ease of synthesis, but this structural motif tends to impart less-than-ideal pharmacokinetic properties and potential metabolism-derived toxicities.…”

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confidence: 68%

“…During analogue design, compounds biased to reside in the cis conformation were prioritized because the cocrystal structure of 3 suggested that this would best mimic the planar aromatic ring seen in the early leads 2 and 3 ( Figure 1 ). 14 Subsequent conformational analysis showed that cis -cyclohexanes would have a strong energetic bias to reside in conformer I , thereby avoiding 1,3-diaxial strain from the 1,3-disubstitution ( Figure 2 ), and this was supported by molecular dynamics simulations. Molecular modeling predicted conformer I to bind well in the ligand pocket compared with the trans -cyclohexane in conformers III and IV , where the conformational changes of the ligand binding site would be less tolerated because of the axial substituent (see the Supporting Information ).…”

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confidence: 87%

“…The importance of reducing the basicity of the piperazine nitrogen with an electron-withdrawing group became apparent in our previous efforts to optimize the potency, selectivity, and PK properties of this early series. 14 Indolylcarboxamides 2 and 3 had been identified as promising leads with potent in vitro activity; however, translating that to in vivo potency proved to be challenging. In our cellular assay, indolylcarboxamide 3-F (SETD2 biochemical IC 50 = 12 nM and H3K36me3 ICW IC 50 = 41 nM), a close analogue of 3 , was 6-fold more potent than 2 (SETD2 biochemical IC 50 = 18 nM and H3K36me3 ICW IC 50 = 235 nM), which lacked the electron-withdrawing group.…”

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confidence: 99%

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Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

Alford

Lampe

Brach

et al. 2022

ACS Med. Chem. Lett.

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SETD2, a lysine N -methyltransferase, is a histone methyltransferase that plays an important role in various cellular processes and was identified as a target of interest in multiple myeloma that features a t(4,14) translocation. We recently reported the discovery of a novel small-molecule SETD2 inhibitor tool compound that is suitable for preclinical studies. Herein we describe the conformational-design-driven evolution of the advanced chemistry lead, which resulted in compounds appropriate for clinical evaluation. Further optimization of this chemical series led to the discovery of EZM0414, which is a potent, selective, and orally bioavailable inhibitor of SETD2 with good pharmacokinetic properties and robust pharmacodynamic activity in a mouse xenograft model.

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confidence: 68%

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confidence: 87%

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confidence: 99%

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Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

Alford

Lampe

Brach

et al. 2022

ACS Med. Chem. Lett.

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“…Given the observation that H3K27me3 aberrantly spreads into H3K36 methylated regions, we tested whether inhibition of SETD2, the only known methyltransferase to deposit H3K36me3 and a PRC2 antagonist, could enable H3K27me3 spreading and halt DLBCL proliferation. We treated a panel of EZH2-wt and -mutant lymphoma cell lines with SETD2-IN-1, a recently disclosed, selective SETD2 inhibitor ( 30 ). Of the seven EZH2-mutant cell lines tested, six were sensitive to SETD2-IN-1 in comparison to only one of the four EZH2-wt cell lines ( Fig.…”

Section: Main Textmentioning

confidence: 99%

Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma

Kwok

Freedy

Siegenfeld

et al. 2022

Preprint

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Cancer mutations in Polycomb Repressive Complex 2 (PRC2) drive aberrant epigenetic states. Although therapies inhibiting the PRC2 enzymatic component EZH2 are FDA-approved, oncogene-specific dependencies remain to be discovered. Here, we identify mutations that confer both resistance and drug addiction to PRC2 inhibitors in EZH2-mutant lymphoma, resulting in cancer cells that paradoxically depend on drug for survival. Drug addiction is mediated by hypermorphic mutations in the CXC domain of EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Drug removal leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Activating EZH2 cancer mutations establish an epigenetic state precariously close to this ceiling, which we show can be breached by inhibition of SETD2, a PRC2 antagonist, to block lymphoma growth. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

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“…Therefore, the targeting of SETD2 is a potential candidate for combination therapies with Tip60 or ATM inhibitors, which can become novel therapeutic strategies for cancer treatment. Recently, a fist-in-class inhibitor, EPZ-719, was reported and is in preclinical validation studies [ 53 ].…”

Section: Histone Methylationmentioning

confidence: 99%

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Lazo

2022

Cancers

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Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

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Discovery of a First-in-Class Inhibitor of the Histone Methyltransferase SETD2 Suitable for Preclinical Studies

Cited by 20 publications

References 18 publications

Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies

Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

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