Next-Generation PARP1 Inhibitors with Enhanced Anticancer Activity
Olaparib–thiodiazole hybrid molecules designed to overcome resistance and enhance anticancer activity.
Starting this week, we will be posting weekly updates on this project and its progress. Each update will highlight what has changed in the project sections, the steps we have taken, and what comes next, so you can follow the work in real time. Today we have refreshed several parts of the project to reflect its current status. We are committed to keeping this weekly update cycle, so that our donors and partners always have a clear and confident view of how the project is moving forward.
Today, the core team for the PARP1-inhibitor project has been reassembled. This group includes the specialists who originally launched the initiative and know its foundations well. With the primary team now in place, the project is moving into its next phase of full-scale development.
Problem
PARP1 inhibitors such as olaparib have transformed the treatment of BRCA-mutated ovarian, breast, and prostate cancers, but they still face serious limitations. Many tumors without BRCA mutations respond poorly, and even initially sensitive cancers often develop resistance by restoring DNA repair or rerouting survival pathways. Traditional drug combinations can increase toxicity and drug–drug interactions, and there is still no dual-acting small molecule that unites PARP1 inhibition with broader anticancer mechanisms in a single, well-controlled scaffold.
Solution
This project designs and synthesizes hybrid molecules that merge the pharmacophore of olaparib with biologically active thiodiazole derivatives. These hybrids are engineered to block PARP1-driven DNA repair while simultaneously disrupting key oncogenic pathways such as PI3K/AKT/mTOR and apoptosis regulation. Using computer-aided drug design, modern organic synthesis, and in vitro testing on BRCA-mutated and non-mutated cancer cell lines, the team will identify lead candidates with enhanced potency, better selectivity, and improved drug-like properties. The ultimate goal is to deliver next-generation PARP1-based agents with real potential to become future preclinical and clinical drug candidates.
Cancer remains a leading cause of death worldwide, and resistance to existing therapies is one of the main reasons treatments fail. PARP1 inhibition has proven the power of synthetic lethality in BRCA-mutated tumors, but its reach is still too narrow and its benefits can fade over time. Patients with BRCA-wild-type tumors, mixed genetic backgrounds, or relapsed disease need options that go beyond single-target strategies.
Hybrid molecules that unite the strengths of olaparib and thiodiazoles offer a way to widen the impact of PARP1-targeted therapy. By attacking DNA repair and survival pathways together, they may work in tumors that currently do not respond to PARP inhibitors and help delay or overcome resistance. This can translate into more durable responses, better use of existing chemotherapies, and a larger population of patients who can benefit from precision oncology.
The project follows a rational drug discovery pipeline. First, the team uses computer-aided drug design tools to build and evaluate virtual hybrids that combine key structural elements of olaparib and thiodiazole compounds. Docking, pharmacophore modeling, and ADME prediction are used to select the most promising candidates for synthesis.
Next, chemists synthesize a focused library of approximately twenty to twenty five hybrid molecules, using multistep organic reactions and modern coupling strategies. Each compound is fully characterized by nuclear magnetic resonance, mass spectrometry, chromatography, and stability tests.
In parallel, biologists test the hybrids in vitro. They measure PARP1 inhibition, assess cytotoxicity in BRCA-deficient and BRCA-proficient cancer cell lines, and compare effects on normal cells. Mechanistic assays track DNA damage, apoptosis, and changes in signaling pathways. Structure–activity relationship analysis then guides optimization, narrowing the set down to a small number of lead candidates with the best balance of potency, selectivity, and drug-like features.
The program focuses on the design, synthesis, and in vitro evaluation of olaparib–thiodiazole hybrid molecules as next-generation PARP1-based anticancer agents. It is a three-year, laboratory-based project with no in vivo or clinical studies in the current phase.
Scope includes:
• computational design and prioritization of hybrid scaffolds;
• synthesis and full physico-chemical characterization of a diverse hybrid library;
• in vitro testing in BRCA-mutated and non-mutated cancer cell lines and normal cells;
• early ADME and toxicity profiling to identify realistic preclinical leads;
• preparation of a clear roadmap for future in vivo and translational studies once lead compounds are confirmed.
• A set of new hybrid molecules that show stronger anticancer activity than olaparib alone in relevant cancer models.
• Identification of one or two lead candidates with promising potency, selectivity, and drug-like properties suitable for further preclinical development.
• Detailed structure–activity relationship data linking chemical features to biological effects and safety.
• Peer-reviewed publications and conference presentations that advance the field of hybrid PARP1 inhibitors.
• A foundation for patent applications and follow-on projects aimed at animal studies and early translational work.
The technical backbone of the project is an integrated platform that combines medicinal chemistry, computational modeling, and experimental pharmacology.
Key components:
• computer-aided design of hybrids using docking, pharmacophore modeling, and in silico ADME/Tox prediction;
• multistep synthesis of olaparib–thiodiazole conjugates using modern coupling reactions and heterocycle chemistry;
• analytical characterization with NMR, MS, HPLC, and stability assays to confirm identity, purity, and behavior in biological media;
• enzyme assays to test PARP1 inhibition;
• cell-based assays for viability, apoptosis, DNA damage markers, and pathway signaling in cancer and normal cell lines;
• early ADME studies, including metabolic stability, permeability, and plasma protein binding, supported by cheminformatics and machine learning tools.
The scientific concept, work plan, and interdisciplinary team are fully defined. The project builds on strong prior experience in PARP1 inhibitor design, hybrid molecule development, and bioactive thiodiazole chemistry within the participating institutions. Core methods in computational modeling, synthesis, and in vitro testing are already established in partner laboratories.
The next step is to secure funding to launch the three-year research program. Once supported, the team will begin with computational design and synthetic route development, followed by staged synthesis, testing, and optimization to move the most promising hybrids toward preclinical candidacy.
We invite donors, research partners, and industry collaborators who are committed to advancing smarter, more resilient cancer therapies. Support for this project will accelerate the creation of dual-acting PARP1-based drug candidates that can address resistance and expand treatment options for patients with aggressive solid tumors.
By joining this effort, partners help move innovative chemistry and rigorous in vitro science toward future targeted therapies, building a bridge from benchtop discovery to potential clinical impact in oncology.
