Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG) - PubMed (original) (raw)

. 2011 Aug 11;54(15):5403-13.

doi: 10.1021/jm200325s. Epub 2011 Jul 8.

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Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)

Jamin D Steffen et al. J Med Chem. 2011.

Abstract

The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.

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Figures

Figure 1

Figure 1

Key pharmacophoric elements related to PARG inhibition

Figure 2

Figure 2

Depletion of NAD(H) in SCC-25 cells following genotoxic stress: (A) Treatment with varying concentrations of MNNG for 30 minutes; (B) A time course of NAD(H) levels following treatment with MNNG (5μg/mL); (C) Effects on NAD(H) depletion in cells treated with MNNG (5μg/mL) for 30 minutes, pretreated with 1mM of benzamide (Bz), 6a, 8d, 6b, or 7.

Figure 3

Figure 3

PAR formation in SCC-25 cells following genotoxic stress: (A) Time course of PAR formation after treatment of MNNG (5μg/mL). Cells were treated with 1mM benzamide with compound 6a (□) and without compound 6a (△) at 20 minutes as indicated by the arrow; (B) Time course of PAR formation following treatment of MNNG (5μg/mL), pretreated with 1mM compound 6a (□) and without pretreatment (■).

Scheme 1

Scheme 1

Synthesis of A-ring, B-ring, and C-ring substituted analogues.a _a_Reagents and Conditions: (i) HO-R, Cs2CO3, 90°C, 24 hrs; (ii) SnCl2, EtOH, 70°C, 3 hrs; (iii) CH3I, acetone, K2CO3, reflux, 3 hrs; (iv) SOCl2, 100°C, 30 min; (v) CH2Cl2, RT; (vi) NH4OH, CH2Cl2, RT; (vii) H2N-R, ether, RT.

Scheme 2

Scheme 2

Synthesis of linker modified analogues.a _a_Reagents and Conditions: (viii) 3,5-dichloro-salicylaldehyde, EtOH; (ix) NaCNBH3, EtOH; (x) CH3I, acetone, K2CO3, reflux 3 hrs; (xi) 5a, CH2Cl2, RT.

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