Synthetic Lethality through the Lens of Medicinal Chemistry

Abstract

Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.

Figure 1

Schematic representation of PARP’s role in SSB and DSB repair. Upon formation of a SSB, PARP1 and other acceptor proteins (histone H1, TOP1, and others) are recruited and attached to the lesion site. This recruits other factors involved in DNA repair (Polβ, LigIII, TDP1, and XRCC1) which, through BER, repair the lesion. If PARP is inhibited, the SSB becomes a DSB which causes γH2AX foci formation, which in the presence of BRCA1/2 triggers HR which repairs the DSB. In the absence of BRCA this break becomes synthetically lethal. Adapted from Clinical Cancer Research, Copyright 2010, Vol. 16, Issue (18), , Page 4532, Christophe E. Redon, Asako J. Nakamura, Yong-Wei Zhang, Jiuping (Jay) Ji, William M. Bonner, Robert J. Kinders, Ralph E. Parchment, James H. Doroshow, Yves Pommier, Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers , with permission from AACR.

Figure 2

Approved PARP inhibitors.

Figure 3

Demonstration of ATM, ATR, and DNA-PKcs involvement in DNA repair networks. Adapted from Trends in Cancer, Vol. 4, Issue (11), , Omar L. Kantidze, Artem K. Velichko, Artem V. Luzhin, Nadezhda V. Petrova, Sergey V. Razin, Synthetically Lethal Interactions of ATM, ATR, and DNAPKcs , Page 762, Copyright (2018) with permission from Elsevier.

Figure 4

(A) SAR study around ATR inhibitor VE-821 (5) to get VX-970 (6). (B) Structure of ATR inhibitor M4344 (7). (C) Structure of BAY1895344 (8) identified by Bayer AG as a selective ATR inhibitor.

Figure 5

Chemical modifications introduced in AZ20 (9) to improve solubility and reduce CYP3A4 activity.

Figure 6

(A) Hit compounds from Ramachandran et al. (B) Optimization of 12 to 16.

Figure 7

(A) Development of ATM inhibitor LY294002 (17) into KU-60019 (20). (B) Structure of ATM inhibitor CP466722 (21).

Figure 8

Development by AstraZeneca of ATM inhibitor from hit 22 into candidate AZD1390 (29) through the lead AZD156 (28).

Figure 9

Structure of SU-11752 (30) and wortmannin (31).

Figure 10

Optimization of PI3K inhibitor 17 resulting in the discovery of KU-5788 (34).

Figure 11

(A) Optimization of DNA-PK inhibitor 35 to AZD7648 (36) by AZ. (B) Structure of DNA-PK inhibitor M3814 (37) developed by Merck.

Figure 12

Optimization of mTOR inhibitor CC214-1 (38) leading to the discovery of mTOR/DNA-PK dual inhibitor CC-115 (39). Small substituents in the N1/N4 position resulted in the maintenance of high potency but improved PD/PK properties.

Figure 13

(A) SAR and optimization of WEE1 inhibitor 40 to 43. (B) Structure of ATR inhibitor ETP-46464 (41). (C) Structure of first WEE1 inhibitor PD0166285 (42).

Figure 14

Optimization of CDK12 inhibitor 44 to 46.

Figure 15

Cocrystallization of 48 with CDK12 adapted from Zhang et al. (a) 48 binds to M816 in the kinase hinge region and connects to Cys1039 in two conformations via the compound’s flexible linker. Solvent-exposed regions of 48 with poor electron density are represented by thin sticks. (b) Omit map contoured at 2.5σ for 48 bound to CDK12 chain C. (c) Omit map contoured at 2.5σ for 48 bound to CDK12 chain D. Reproduced with permission from Springer Nature, Nature Chemical Biology, Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors, Tinghu Zhang, Nicholas Kwiatkowski, Calla M. Olson, Sarah E. Dixon-Clarke, Brian J. Abraham, Ann K. Greifenberg, Scott B. Ficarro, Jonathan M. Elkins, Yanke Liang, Nancy M. Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L. Greenleaf, Jarrod A. Marto, Matthias Geyer, Alex N. Bullock, Richard A. Young, Nathanael S. Gray. , Copyright 2019 Springer Nature.

Figure 16

(A) Optimization of CDK inhibitor THZ1 (47). (B) Structure of CDK inhibitor dinaciclib (49).

Figure 17

(A) PARP inhibitors triggering synthetic lethality in BRCA-deficient cells. (B) Proposed triggering of small molecule-induced synthetic lethality using PARP inhibitors in combination with RAD51-BRCA2 disruptors. Adapted from European Journal of Medicinal Chemistry, Vol. 165, Marinella Roberti, Fabrizio Schipani, Greta Bagnolini, Domenico Milano, Elisa Giacomini, Federico Falchi, Andrea Balboni, Marcella Manerba, Fulvia Farabegoli, Francesca De Franco, Janet Robertson, Saverio Minucci, Isabella Pallavicini, Giuseppina Di Stefano, S. Girotto, R. Pellicciari, A. Cavalli, Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells , Page 81, Copyright (2019), with permission from Elsevier.

Figure 18

Depiction of the SAR strategy for the further development of 52. This primarily focused on three areas within the molecule highlighted in green, red, and blue. The proposed moieties in these regions are shown in their accompanying text.

Figure 19

Optimization of 53 to 54. All compounds from this series were tested as racemic mixtures after both enantiomers of 53 showed the same biochemical activity and binding mode.

Figure 20

Examples of Rad51 inhibitors reported in the literature.

Figure 21

RAD52, SL interactions with PARP inhibitors. This figure shows classic SL with PARP inhibition in BRCA2 deficient-cancer cells. These are prone to acquired mutation. The implementation of RAD52 in combination with PARPi has no effect in BRCA2 proficient healthy cells; however, in BRCA2-deficient cancer cells, small-molecule-induced synthetic lethality occurs. Adapted from Cancers, 2019, Vol. 11, Issue (10), , Monika Toma, Katherine Sullivan-Reed, Tomasz Śliwiński, Tomasz Skorski, RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies , Page 1569, with use of the Attribution 4.0 International (CC BY 4.0) open access license.

Figure 22

Structures of different RAD52 inhibitors.

Figure 23

Proposed binding regions of the RAD52 inhibitors: (A) 63 and (B) 64. Adapted from eLIFE, 2016, Vol. 5, e14740, Sarah R. Hengel, Eva Malacaria, Laura Folly da Silva Constantino, Fletcher E. Bain, Andrea Diaz, Brandon G. Koch, Liping Yu, Meng Wu, Pietro Pichierri, M. Ashley Spies, Maria Spies, Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells , with use of the Attribution 4.0 International (CC BY 4.0) open access license.

Figure 24

Proposed binding regions of 66. Reproduced with permission of The Royal Society of Chemistry, from Li J.; Yang Q.; Zhang Y.; Huang K.; Sun R.; Zhao Q.. Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association. RSC Advances, Vol. 8, Issue (34), , pp 18859–18869, Copyright 2018, permission conveyed through Copyright Clearance Center, Inc.