Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines

Katayama, Katsushi; Ishii, Ken J.; Tsuda, Eisuke; Yotsumoto, Keiichi; Hiramoto, Kumiko; Suzuki, Makoto; Yasumatsu, Isao; Igarashi, Wataru; Torihata, Munefumi; Ishiyama, Takashi; Katagiri, Takahiro

doi:10.1016/j.bmcl.2020.127475

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…Insertion of the tetrahydroazepine group as a side chain, used successfully in the design of 33 , allowed the identification of 35 , with increased potency on G9a/GLP (IC 50 of 4.3 and 32.3 nM, respectively) compared with 34 and an improved PK profile in mice (the oral bioavailability increased up to 40%). 89…”

Section: Introductionmentioning

confidence: 99%

Lysine methyltransferase inhibitors: where we are now

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Lysine methyltransferase inhibitors: where we are now

et al. 2022

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“…Considering their unique physiological and pathophysiological functions, EHMT1/2 have emerged as cancer therapeutic targets and, as such, inhibitors targeting G9a and GLP evolved as a novel approach to cancer treatment [ 97 , 98 , 99 ]. Some of the examples of G9a/GLP inhibitors include BIX-01294, UNC0638, UNC0642, DS79932728, and compound 20 ( Figure 24 ) [ 99 , 100 , 101 ].…”

Section: Synergistic Effect Of the Dual Inhibition/hybrid Approachmentioning

confidence: 99%

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

Dhuguru

Ghoneim

2022

Molecules

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Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.

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“…In the above-mentioned report, 20 we described the discovery of the tetrahydroazepine side chain as a novel motif for a Lys binding site, where a 3-(pyrrolidin-1-yl)propoxy group had usually been used. To examine the versatility of this side chain, we introduced it to the other central cores of known G9a/GLP inhibitor series (Table 1).…”

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confidence: 99%

“…Moreover, completely distinct classes of compounds that inhibit G9a/GLP have been identified, such as aminoindole A-366 ( 4 ) and 2-aminobenzimidazole ( 5 ) . We previously reported the discovery of a novel potent G9a/GLP inhibitor ( 6 ) with a fixed cyclic side chain . Here, we report on our efforts to further develop this inhibitor to increase its potency and to improve its absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties to exhibit in vivo efficacy at a low predicted dose.…”

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confidence: 99%

“…Subsequent regioselective nitration with nitric acid followed by removal of the benzyl group using Pd/C and cyclohexadiene afforded compound 27 . Triflation of compound 27 followed by Suzuki-Miyaura coupling with boronic acid pinacol ester ( 29 ) afforded compound 30 . Removal of the tert -butoxycarbonyl group under acidic conditions followed by N -methylation led to compound 32 .…”

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Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease

Katayama

Ishii

Terashima

et al. 2020

ACS Med. Chem. Lett.

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Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.

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Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines

Cited by 18 publications

References 33 publications

Lysine methyltransferase inhibitors: where we are now

Lysine methyltransferase inhibitors: where we are now

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease

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