Synthesis of lysine methyltransferase inhibitors

Abstract

Lysine methyltransferase which catalyze methylation of histone and non-histone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

Keywords: S-adenosyl-l-methionine; epigenetics; inhibitors; lysine methyltransferase; synthesis.

Figure 1

(A) Mechanism of DOT1L in methylation of lysine moiety of protein H3K79. (B) Specific lysine methyl transferase methylated lysine residues in histone lysine tail.

Figure 2

Example of inhibitors targeting protein Suv39H1.

Scheme 1

(A) Total synthesis of (+)-Chaetocin A and its S-deficient analog by Sodeoka et al. (B) Total synthesis of (+)-Chaetocin A by Movassaghi and co-workers.

Figure 3

Example of inhibitors targeting protein G9a-GLP.

Scheme 2

Development of G9a-GLP inhibitors by Jin and co-workers.

Scheme 3

(A) Synthesis of BIX-01294 by Liu et al. (B) Synthesis of UNC0224 and UNC0321 by Liu et al. (C) Synthesis of UNC0638 by Vedadi et al.

Scheme 4

(A) Synthesis of UNC0642 by Liu et al. (B) Synthesis of UNC0965 by Konze et al. (C) Synthesis of E72 by Chang et al.

Scheme 5

(A) Synthesis of A366 by Sweis et al. (B) Synthesis of BRD9539 by Yuen et al. (C) Synthesis of HKMTI-1-248 by Srimongkolpithak et al.

Figure 4

Example of inhibitors targeting protein EZH.

Scheme 6

(A) Synthesis of EPZ005687 by Kuntson et al. (B) Synthesis of GSK126 by McCabe et al.

Scheme 7

(A) Synthesis of GSK926 and GSK343 by Verma et al. (B) Synthesis of UNC1999 by Konze et al.

Scheme 8

Synthesis of Garapaty-Rao cmp3 by Nasveschuk et al.

Figure 5

Example of inhibitors targeting protein DOL1L.

Scheme 9

Synthesis of EPZ004777 by Basavapathruni et al.

Scheme 10

(A) Synthesis of EPZ004777 and SGC0946 by Yu et al. (B) Synthesis of EPZ003696 by Basavapathruni et al.

Scheme 11

(A) Synthesis of Yao cmp4 by Yao by Yu et al. (B) Synthesis of BrSHA by Yu et al. (C) Synthesis of EPZ5676 by Olhava et al.

Figure 6

Example of inhibitors targeting protein SETD8.

Scheme 12

Synthesis of UNC0379 by Ma et al.