Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

Abstract

Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.

Keywords: CRISPR/Cas9; Cancer; Epigenetics; Inhibitors; Mechanisms; Multitargeting; PROTACS; Scaffolds.

Fig. 1

FDA and CFDA approved inhibitors of the epigenetic targets

Fig. 2

DNA methyl transferase inhibitors (nucleoside and non-nucleoside based)

Fig. 3

EZH2 inhibitors

Fig. 4

Pinometostat

Fig. 5

HDAC inhibitors

Fig. 6

LSD1 inhibitors

Fig. 7

BET inhibitors

Fig. 8

PROTAC design

Fig. 9

Toolbox of ligands for E3 ligases

Fig. 10

Epigenetic inhibitor based PROTACs

Fig. 11

Design of dual HDAC-HSP90 inhibitor

Fig. 12

Design of dual HDAC-DNMT inhibitor

Fig. 13

Design of dual HDAC-DNMT inhibitor

Fig. 14

Design of dual HDAC-BET inhibitor

Fig. 15

Design of dual HDAC-EZH2 inhibitor

Fig. 16

Design of dual HDAC-PI3K inhibitor

Fig. 17

Design of dual HDAC-tubulin inhibitor

Fig. 18

CAP rigidification approach

Fig. 19

CAP modification

Fig. 20

CAP modification

Fig. 21

Clinically and preclinically active HDAC inhibitors

Fig. 22

Ring opening strategy

Fig. 23

Classification on the basis of zinc binding motif

Fig. 24

Fragment stitching approach

Fig. 25

Antibody drug conjugates