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PARP/PARG Screening & Profiling Service

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Within the DNA damage repair (DDR) network, the PARP family has evolved from classical DNA repair regulators into one of the central targets in precision oncology. Meanwhile, PARG, as a functional antagonist of PARP-mediated signaling, is emerging as a critical component of next-generation regulatory strategies. As PARP inhibitors enter a clinically mature phase, systematic investigations centered on "PARP inhibition – PARG modulation – resistance mechanisms" are becoming a new focal point in DDR drug development.

Overview

PARP catalyzes PARylation to regulate DNA repair and replication stress, while PARG hydrolyzes PAR chains to maintain a dynamic balance. Together, they form a highly plastic regulatory axis. In HRD tumors, PARP inhibitors have achieved success via synthetic lethality, but resistance driven by HR restoration, fork protection, and altered PARP trapping is shifting strategies toward dual PARP/PARG modulation.

Leveraging extensive DDR expertise, Creative Biogene has established an integrated platform spanning PARP and PARG dual targets—from enzymatic activity to cellular function and translational applications—enabling clients to move seamlessly from target understanding to clinical feasibility validation.

From DNA Repair Mechanism to Drug Discovery Opportunity

Members of the PARP family (particularly PARP1/2) are rapidly recruited to DNA damage sites, where they catalyze PAR chain formation to recruit DNA repair proteins. PARG, in turn, hydrolyzes PAR chains to restore protein states. This dynamic cycle not only regulates DNA repair efficiency but also impacts transcription, inflammatory signaling, and cell fate decisions.

Figure 1. PARP1 activation at DNA damage sites. (Gopal AA, et al., 2024)

Importantly, the clinical efficacy of PARP inhibitors depends not only on catalytic inhibition but also on their ability to induce PARP trapping—stabilizing PARP at DNA damage sites, thereby blocking repair and inducing cytotoxicity. This introduces a higher standard for drug screening: it is no longer sufficient to measure inhibition alone; trapping capacity must also be quantified.

Meanwhile, PARG inhibition is emerging as a complementary strategy. By enhancing PAR accumulation, increasing replication stress, or altering repair pathway choice, PARG targeting may generate synergistic or alternative therapeutic effects in specific contexts.

Fully Integrated PARP/PARG Assay & Screening Service

Unlike conventional service models that focus solely on single enzymatic assays or basic screening, our platform is mechanism-driven, providing systematic analysis of the PARP/PARG axis across enzymology, cellular function, and translational relevance.

Dual-Target Functional Profiling

We have established a comprehensive functional profiling system covering both PARP and PARG, enabling multidimensional drug evaluation:

  • PARP1/2 enzymatic activity assays (fluorescence- or luminescence-based PARylation readouts)
  • PARG hydrolytic activity assays (PAR degradation kinetics analysis)
  • Quantification of PARP trapping capacity (DNA-binding stability and complex formation analysis)
  • PARP family selectivity profiling (PARP1 vs PARP2 vs PARP3)
  • Evaluation of PARG inhibition effects and intracellular PAR accumulation

This integrated system is particularly valuable for distinguishing catalytic inhibitors from trapping-enhancing compounds, addressing a major gap in traditional screening strategies.

Functional Assays Across the DDR Network

To better reflect real biological responses, enzymatic assays are extended into pathway- and cell-based functional analyses:

  • Dynamic monitoring of ADP-ribosylation levels (intracellular PAR signals)
  • DNA repair pathway selection analysis (HR vs NHEJ vs alt-EJ)
  • Replication fork stability and replication stress assessment
  • DNA damage markers (γH2AX, 53BP1) quantification
  • Transcriptional regulation and chromatin accessibility analysis

These readouts not only elucidate mechanisms of action but also provide critical insights for predicting clinical response.

PARP/PARG Inhibitor Screening & Optimization

We offer a full workflow from primary screening to mechanistic characterization:

High-Throughput Screening (HTS)

Our HTS platform supports automated 96/384-well screening with multiple detection modes, including fluorescence and luminescence, enabling multi‑channel detection of PARP activity, PARG activity, and PAR accumulation.

ONE

Hit Validation & Mechanistic Deconvolution

  • IC50 / EC50 determination
  • Target engagement validation (SPR / NanoBRET)
  • PARP trapping capability assessment
  • PARP/PARG dual-target selectivity profiling
TWO

Resistance Mechanism Analysis

  • HR restoration analysis
  • Replication fork protection mechanism studies
  • DDR pathway reprogramming profiling
  • Long-term drug-induced resistance model development
THREE

Combination Strategy Development

  • PARP + PARG dual inhibition
  • PARP + ATR / DNA-PK combinations
  • PARP + DNA-damaging agents

What You Need and How We Deliver

Know if your compound truly traps PARP

Enzyme IC50 alone is misleading. We run a tiered cascade: activity, DNA binding, chromatin retention, and cell damage. You get a clear verdict: inhibitor, trapper, or both.

Anticipate and break resistance

PARPi often upregulates PARG or NHEJ. We measure compensation and fork stability, then test combinations (PARP+PARG, PARP+ATR, PARP+WEE1) before resistance derails your program.

Don't chase false leads

Many hits fail in cells due to cytotoxicity or poor engagement. Our early counter‑screens filter artefacts before costly in vivo studies.

Pay only for what you need

Single assay, modular package, or full HTS‑to‑lead. Clear go/no‑go gates at each step. No black boxes.

Empowering Next-Generation DDR Therapeutics

As PARP inhibitors reach maturity, DDR drug development is shifting toward mechanistic refinement and combinatorial strategies. Dual targeting of PARP and PARG not only offers new avenues to overcome resistance but also lays the foundation for next-generation precision oncology.

Creative Biogene is committed to translating complex DDR biology into actionable drug discovery strategies, enabling clients to progress from target validation to clinical translation in a highly competitive therapeutic landscape.

FAQ

1. Is it necessary to study PARP and PARG together?

Not necessarily, but combined analysis is recommended when resistance or mechanisms are involved. Long‑term PARP inhibition can upregulate PARG, and PARP alone may not fully suppress PAR dynamics. PARP synthesizes PAR while PARG degrades it; ignoring PARG may miss critical effects on PAR turnover. For routine screening, starting with PARP is fine, but add PARG when tackling resistance or combination therapy.

2. How can I determine whether a compound has PARP trapping activity?

Trapping cannot be inferred from enzyme IC50 alone. Use a tiered approach: confirm catalytic inhibition, then assess PARP‑DNA complex stability (EMSA/SPR), followed by chromatin retention (gold‑standard Western), and finally cellular damage readouts (comet, γH2AX). Only this multi‑layer data reliably classifies a compound as an inhibitor, trapper, or both.

3. Can I skip enzymatic assays and directly screen in cell or animal models?

Possible but not recommended. Skipping enzyme assays risks false positives from non‑specific cytotoxicity and leaves the mechanism unclear. Enzymatic data also guides medicinal chemistry for SAR optimization. Best practice: start with enzyme screening (PARP1/2 IC50), then proceed to trapping, cellular, and in vivo steps. If you must skip, at least include target engagement validation (SPR/CETSA).

References:

  1. Wang C, Zhang H, Liu Q, Li J, Chen Y. PASTA: PARP activity screening and inhibitor testing assay. Nat Commun. 2021;12(1):1029.
  2. Zandarashvili L, Langelier MF, Velagapudi UK, et al. PARP trapping activity correlates with clinical efficacy of PARP inhibitors. Cancer Res. 2020;80(5):1234–1245.
  3. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152–1158.
  4. Gopal AA, Fernandez B, Delano J, et al. PARP trapping is governed by the PARP inhibitor dissociation rate constant. Cell Chem Biol. 2024 Jul 18;31(7):1373-1382.e10.
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