ArticleJournal of the American Chemical Society2026
Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy.
Tian Qiu, Yeuan Ting Lee, Brendan G Dwyer, Yi Jer Tan, Ting Chen, Bryan A Romero, Yanlan Wang, Jiehui Deng, Tinghu Zhang, Gerald R Crabtree and 3 more
Abstract read
In one paragraphArticle in Journal of the American Chemical Society, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
13 authors.
Tian QiuDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.ORCID 0000-0002-7168-0715 Yeuan Ting LeeLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York 10016, United States.
Brendan G DwyerDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.ORCID 0000-0001-8593-4184 Yi Jer TanLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York 10016, United States.
Ting ChenLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York 10016, United States.
Bryan A RomeroDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.
Yanlan WangDepartment of Pathology, Stanford University, Stanford, California 94305, United States.
Jiehui DengLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York 10016, United States.
Tinghu ZhangDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.ORCID 0000-0003-1028-8020 Gerald R CrabtreeDepartment of Pathology, Stanford University, Stanford, California 94305, United States.ORCID 0000-0001-9685-7911 Stephen M HinshawDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.ORCID 0000-0003-4215-5206 Kwok-Kin WongLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York 10016, United States.
Nathanael S GrayDepartment of Chemical and Systems Biology, ChEM-H and Stanford Cancer Institute, Stanford Medical School, Stanford University, Stanford, California 94305, United States.ORCID 0000-0001-5354-7403 Funding
HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCLR01CA276167 · NCI · STANFORD UNIVERSITY · PI Gerald R. Crabtree, NATHANAEL Schiander GRAY · 2023 to 2026
$2.2MREWIRING ONCOGENIC PATHWAYS TO INDUCE CELL DEATH IN CHRONIC LYMPHOCYTIC LEUKEMIAR01CA304428 · NCI · STANFORD UNIVERSITY · PI Gerald R. Crabtree, Neil E Kay · 2026 to 2026
$661kNCI NIH HHS R01 CA276167NCI NIH HHS R01 CA304428
6 · The paper itselfAbstract
Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair, particularly in homologous recombination-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 chemically 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 DDR and apoptosis in cancer cells 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
Indexed as
Antineoplastic AgentsDNA DamageDrug DesignNeoplasmsPoly(ADP-ribose) Polymerase InhibitorsAnimalsApoptosisBromodomain Containing ProteinsCell Cycle ProteinsCell Line, TumorCell ProliferationDrug Screening Assays, AntitumorHumansMiceMolecular StructureTranscription FactorsAntineoplastic AgentsBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsPoly(ADP-ribose) Polymerase InhibitorsTranscription Factors
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