Brendan Dwyer

All Publications

• Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability. Blood Sekrecki, M., Sekrecka, A., Lattupally, R. R., Le, K., Jin, X., Mozes, C., Dwyer, B. G., Zhuang, Z., Romero, B. A., Pineda, J. M., Cao, X., Nguyen, L., Chen, V. W., Zhou, C., Wallace, J. A., Tanaka, K. L., Tiwari, C., Gabel, A., Kim, W. J., Stanley, R. F., Benbarche, S., Thind, J., Muruganandham, A., Zhang, T. Y., Greenberg, P. L., Gotlib, J., Mannis, G. N., Shomali, W., Salmasi, G. G., Kuo, C. J., Shanafelt, T. D., Singh, I., Inoue, D., Hansen, F. K., Gray, N. S., Van Rechem, C., Fakhri, B., Zhang, X., Lu, S. X. 2026

  Abstract

  Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL) and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of mRNA protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss-of-function, thus contributing to cancer pathogenesis.Here we systematically analyzed the impact of mutant SF3B1 on non-coding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of one target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5' and 3' untranslated regions (5', 3' UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1 mutant cells, representing the first time that oncogenic SF3B1 has been shown to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.

  View details for DOI 10.1182/blood.2025029972

  View details for PubMedID 41587094

• Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy. Journal of the American Chemical Society Qiu, T., Lee, Y. T., Dwyer, B. G., Tan, Y. J., Chen, T., Romero, B. A., Wang, Y., Deng, J., Zhang, T., Crabtree, G. R., Hinshaw, S. M., Wong, K., Gray, N. S. 2026

  Abstract

  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 in vitro, leading to antitumor 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.

  View details for DOI 10.1021/jacs.5c17396

  View details for PubMedID 41480895

• Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase JOURNAL OF MEDICINAL CHEMISTRY Jeon, E., Kim, Y., Ahn, H., Martinez, M. J., Hwang, K., Cho, S., Dwyer, B. G., Romero, B. A., Hinshaw, S. M., Gray, N. S., Sim, T. 2025

  Abstract

  We discovered novel small molecule ligands of KLHDC2 and leveraged them to generate KLHDC2-mediated CDK6-selective degraders. Degrader 48a exhibited potent and selective CDK6 degradation (DC50 = 0.037 μM) over CDK4 (DC50 > 10 μM) in MOLM-14 cells, leading to pronounced G0/G1 cell-cycle arrest and apoptosis through inhibition of CDK6 downstream signaling. In addition, 48a demonstrated superior growth-inhibitory activity compared to the warhead, palbociclib, in several leukemia cells and displayed favorable microsomal stability. Proteomic profiling confirmed that 48a selectively degrades CDK6 with minimal effects on other CDK family members. Furthermore, 48a reduced tumor burden and CDK6 levels in an in vivo xenograft model. Collectively, these findings highlight the potential of KLHDC2-mediated degraders as a novel strategy for selective CDK6 degradation and underscore the promise of KLHDC2 as an alternative E3 ligase platform for targeted protein degradation.

  View details for DOI 10.1021/acs.jmedchem.5c02713

  View details for Web of Science ID 001630007800001

  View details for PubMedID 41329866

• Rewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules. Journal of the American Chemical Society Bond, M. J., Golden, R. P., DiGiovanni, G., Howard, B., Sarott, R. C., Karim, B. A., Gourisankar, S., Alexe, G., Ross, K., Jones, H. M., Dwyer, B. G., Gray, N. S., Stegmaier, K. 2025

  Abstract

  Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules. In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression of BCL6 target genes. This proof-of-concept study demonstrates that DNA binding proteins with pioneering transcription factor activity, such as EWSR1::FLI1, can be relocalized on chromatin to induce expression of repressed genes. Insights herein will guide the development of future bivalent molecules that rewire DNA binding transcriptional machinery.

  View details for DOI 10.1021/jacs.5c05634

  View details for PubMedID 41307210

• Design and Development of DNA Damage Chemical Inducers of Proximity (DD-CIP) for Targeted Cancer Therapy. bioRxiv : the preprint server for biology Qiu, T., Lee, Y. T., Dwyer, B. G., Tan, Y. J., Chen, T., Romero, B. A., Wang, Y., Deng, J., Zhang, T., Crabtree, G. R., Hinshaw, S. M., Wong, K. K., Gray, N. S. 2025

  Abstract

  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.

  View details for DOI 10.1101/2025.11.03.686423

  View details for PubMedID 41278667

  View details for PubMedCentralID PMC12637661

• Novel therapeutics for SF3B1 mutant cancers which exploit the missplicing of DCAF16 Sekrecki, M., Sekrecka, A., Lattupally, R., Le, K., Cao, X., Chen, V., Zhuang, Z., Dwyer, B., Zhou, C., Tiwari, C., Gabel, A., Kim, W., Stanley, R., Benbarche, S., Pineda, J., Gray, N., Zhang, T., Greenberg, P., Gotlib, J., Mannis, G., Shomali, W., Salmasi, G., Shanafelt, T., Van Rechem, C., Zhang, X., Fakhri, B., Lu, S. ELSEVIER. 2025: 1474-1475

  View details for DOI 10.1182/blood-2025-1474

  View details for Web of Science ID 001658978100025

• Therapeutic targeting of the nuclear pore complex with molecular glue degraders in pancreatic cancer Yuan, L., Ji, W., Dwyer, B. G., Lu, J., Bian, J., Colombo, G. M., Martinez, M. J., Fernandez, D., Phillips, N. A., Tang, M. T., Zhou, C. W., Jones, H. M., Calla, N., Huancas, C., Eckart, M., Tran, J., Qiu, T., Doench, J. G., Rees, M. G., Roth, J. A., Cameron, M. D., Charville, G. W., Kuo, C. J., Dixon, S. J., Zhang, T., Hinshaw, S. M., Gray, N. S., Corsello, S. M. AMER ASSOC CANCER RESEARCH. 2025

  View details for DOI 10.1158/1538-7445.PANCREATIC25-B003

  View details for Web of Science ID 001588114400040

• Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex. Cancer discovery Yuan, L., Ji, W., Dwyer, B. G., Lu, J., Bian, J., Colombo, G. M., Martinez, M. J., Fernandez, D., Phillips, N. A., Tang, M. T., Zhou, C. W., Quispe Calla, N. E., Guzman Huancas, C., Eckart, M., Tran, J., Jones, H. M., Qiu, T., Doench, J. G., Rees, M. G., Roth, J. A., Cameron, M. D., Charville, G. W., Kuo, C. J., Dixon, S. J., Zhang, T., Hinshaw, S. M., Gray, N. S., Corsello, S. M. 2025

  Abstract

  Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex. Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the nuclear pore complex. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and x-ray crystallography, while compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.

  View details for DOI 10.1158/2159-8290.CD-25-0271

  View details for PubMedID 40891634

• Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders. Angewandte Chemie (International ed. in English) Gray, N. S., Zhuang, Z., Byun, W. S., Kozicka, Z., Donovan, K., Dwyer, B., Thornhill, A., Jones, H., Jiang, Z., Zhu, X., Fischer, E., Thomä, N. 2025: e202508427

  Abstract

  Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4 associated factor 16 (DCAF16) E3 ligase.

  View details for DOI 10.1002/anie.202508427

  View details for PubMedID 40626960

• A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death. bioRxiv : the preprint server for biology Nix, M. N., Gourisankar, S., Sarott, R. C., Dwyer, B. G., Nettles, S. A., Martinez, M. M., Abuzaid, H., Yang, H., Wang, Y., Simanauskaite, J. M., Romero, B. A., Jones, H. M., Krokhotin, A., Lowensohn, T. N., Chen, L., Low, C., Davis, M. M., Fernandez, D., Zhang, T., Green, M. R., Hinshaw, S. M., Gray, N. S., Crabtree, G. R. 2025

  Abstract

  Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.

  View details for DOI 10.1101/2025.03.14.643404

  View details for PubMedID 40166243

  View details for PubMedCentralID PMC11956963

• Relocalizing transcriptional kinases to activate apoptosis. Science (New York, N.Y.) Sarott, R. C., Gourisankar, S., Karim, B., Nettles, S., Yang, H., Dwyer, B. G., Simanauskaite, J. M., Tse, J., Abuzaid, H., Krokhotin, A., Zhang, T., Hinshaw, S. M., Green, M. R., Crabtree, G. R., Gray, N. S. 2024; 386 (6717): eadl5361

  Abstract

  Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.

  View details for DOI 10.1126/science.adl5361

  View details for PubMedID 39361741

• Discovery of electrophilic degraders that exploit SNAr chemistry. bioRxiv : the preprint server for biology Zhuang, Z., Byun, W. S., Kozicka, Z., Dwyer, B. G., Donovan, K. A., Jiang, Z., Jones, H. M., Abeja, D. M., Nix, M. N., Zhong, J., Słabicki, M., Fischer, E. S., Ebert, B. L., Gray, N. S. 2024

  Abstract

  Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (SNAr) reactions in the rational design of electrophilic protein degraders. Appending an SNAr covalent warhead to several preexisting small molecule inhibitors transformed them into degraders, obviating the need for a defined E3 ligase recruiter. The SNAr covalent warhead is versatile; it can recruit various E3 ligases, including DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 16 (DCAF16), and possibly others. The incorporation of an SNAr covalent warhead into the BRD4 inhibitor led to the discovery of degraders with low picomolar degradation potency. Furthermore, we demonstrate the broad applicability of this approach through rational functional switching from kinase inhibitors into potent degraders.

  View details for DOI 10.1101/2024.09.25.615094

  View details for PubMedID 39386645

  View details for PubMedCentralID PMC11463635

• Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2). Angewandte Chemie (International ed. in English) Ji, W., Byun, W. S., Lu, W., Zhu, X., Donovan, K. A., Dwyer, B., Che, J., Yuan, L., Abulaiti, X., Corsello, S. M., Fischer, E. S., Zhang, T., Gray, N. S. 2023: e202308292

  Abstract

  Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first-in-class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.

  View details for DOI 10.1002/anie.202308292

  View details for PubMedID 37658265