Abstract 3263: Preclinical characterization of PRT3789, a potent and selective SMARCA2 targeted degrader

Hulse, Michael; Agarwal, Anjoo; Wang, Min; Carter, Jack; Sivakumar, Monisha; Vidal, Brian; Brown, Justin; Moore, Andrew W.; Grego, Alexander; Bhagwat, Neha; Rager, Joseph; Lu, Liang; Basch, Corey H.; Bersch, Klare; Dai, Chong; Pitis, Philip; Combs, Andrew P.; Ruggeri, Bruce; Vaddi, Kris; Scherle, Peggy; Ito, Koichi

doi:10.1158/1538-7445.am2022-3263

Cited by 6 publications

(4 citation statements)

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“…A947 suppressed SMARCA4 mutant lung cancer growth in vivo and synergized with an inhibitor to the MCL1 anti-apoptotic protein to enhance apoptosis. PRT3789 is another potent and selective SMARCA2-targeted degrader that demonstrated synthetic lethality in SMARCA4-deficient cancers in vitro and in vivo and is currently in Phase I clinical trials for patients with SMARCA4 mutant solid tumors that express SMARCA2 [127].…”

Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 99%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

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Section: Targeting Swi/snf Family VIII Bromodomainsmentioning

confidence: 99%

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Dreier,

Walia,

de la Serna

2024

Epigenomes

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“…Here, PRT3789 from Prelude Therapeutics offers clear differentiation from these smallmolecule efforts [186]. Biochemically, the heterobifunctional molecule binds at equipotent nanomolar concentrations to both BRG and BRM1, yet delivers 19-fold selectivity in cellbased BRM/BRG1 HiBiT assays.…”

Section: Heterobifunctional Degraders In Oncologymentioning

confidence: 99%

Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders

Bouvier,

Lawrence,

Cavallo

et al. 2024

Cells

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Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

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“…209 Nevertheless, the therapeutic rationale of SMARCA2 degraders in SMARCA4 mutant tumors suggests a promising clinical future, as demonstrated by the VHL-based PROTAC undisclosed by Prelude Therapeutics (PRT3789) that recently entered a phase 1 clinical trial (NCT05639751). 213…”

Section: Sl Beyond Ddrmentioning

confidence: 99%

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Previtali,

Bagnolini,

Ciamarone

et al. 2024

J. Med. Chem.

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In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADPribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.

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Abstract 3263: Preclinical characterization of PRT3789, a potent and selective SMARCA2 targeted degrader

Cited by 6 publications

References 0 publications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

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