⮝ Full datasets listing
PXD071670
PXD071670 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Design and Development of DNA Damage Chemical Inducers of Proximity (DD-CIP) for Targeted Cancer Therapy |
| Description | Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair particularly in homologous recombination (HR)-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce DNA Damage Chemical Inducers of Proximity (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemical induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1 which induces the DNA damage response (DDR) and apoptosis to a range of cancer lines at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to anti-tumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical induced proximity as a strategy for modulating the DDR in cancer. Exp ID # 1050 contains FLAG-BRD4 IP-MS for DD-CIP1 (TWQ-03-052) & TWQ-03-184 (DD-CIP2). 1086 contains FLAG-PARP1 for DD-CIP2 (TQ-03-184). 1103 contains FLAG-PARP1 IP-MS for Olaparib. 1131 contains FLAG-PARP1 IP-MS for DD-CIP1 (TWQ-03-052). |
| HostingRepository | MassIVE |
| AnnounceDate | 2026-02-21 |
| AnnouncementXML | Submission_2026-02-21_09:08:42.131.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Brendan Dwyer |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Carbamidomethyl |
| Instrument | timsTOF HT |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2025-12-06 12:36:49 | ID requested | |
| ⏵ 1 | 2026-02-21 09:08:43 | announced |
Publication List
| Qiu T, Lee YT, Dwyer BG, Tan YJ, Chen T, Romero BA, Wang Y, Deng J, Zhang T, Crabtree GR, Hinshaw SM, Wong KK, Gray NS, Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy. J Am Chem Soc, 148(1):1153-1163(2026) [pubmed] |
Keyword List
| submitter keyword: DNA Damage Chemical Inducers of Proximity, IP-MS, AP-MS, Proximity Therapeutics, Molecular Glues, DatasetType:Proteomics |
Contact List
| Nathanael S. Gray | |
|---|---|
| contact affiliation | Stanford University |
| contact email | nsgray01@stanford.edu |
| lab head | |
| Brendan Dwyer | |
| contact affiliation | Stanford University |
| contact email | dwyermrbrendan@gmail.com |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
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