Kenneth Steadman

Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders

Geoffray Leriche, Farhana Barmare, Julia I. Toth, Aleksandar Jamborcic et autres

High Resolution Image Download MS PowerPoint Slide Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we report the discovery of BRD4-selective monovalent …

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Abstract 7074: PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader, enhances efficacy of standard of care agents in SMARCA4 mutant tumor models.

G. Parker, Geoffray Leriche, Aleksandar Jamborcic, Taylor Kampert et autres

Abstract SMARCA2 and SMARCA4 are mutually exclusive, essential catalytic subunits of human BAF complexes, which are involved in controlling gene expression through the remodeling of chromatin structure. In a subset of solid tumors, SMARCA4 is frequently mutated, rendering cancer cells with SMARCA4 …

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Abstract 404: Mechanistic characterization of selective monovalent direct degraders of SMARCA2

Julia I. Toth, G.J. Parker, Geoffray Leriche, Aleksandar Jamborcic et autres

Abstract SMARCA2 and SMARCA4 are essential, redundant, catalytic subunits of the multi-subunit BRG1/BRM-associated factor (BAF) complex. This complex regulates gene expression and DNA repair through chromatin remodeling activity. The paralogues SMARCA2 and SMARCA4 bind acetylated histones through their highly conserved bromodomains and …

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Abstract 1653: Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader

G.J. Parker, Geoffray Leriche, Aleksandar Jamborcic, Taylor Kampert et autres

Abstract SMARCA2 and SMARCA4 are essential, yet redundant, catalytic subunits of human BAF complexes, which are involved in controlling gene expression through the remodeling of chromatin structure. In a subset of solid tumors, SMARCA4 is commonly mutated, rendering SMARCA4-deficient cancer cells highly …

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Supplementary Table S2 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplementary Table S2 show anti-proliferative activity in AML cell lines (n = 2)

Supplementary Table S4 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplementary Table S4 shows information for the antibodies used in these studies

Supplemental Figure S1 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplemental Figure S1 shows BRD4 degradation kinetics in the HiBiT reporter cell line

Supplementary Figure S3 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplementary Figure S3 shows megakaryocyte colony formation data

Data from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Abstract Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely …

Supplemental Figure S2 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplemental Figure S2 shows PLX-3618 binding data to both bromodomains of BRD4

Supplementary Data from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplementary file containing Figures S1-3 and Tables S1-4

Supplementary Table S1 from Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11

Gregory S. Parker, Julia I. Toth, Sarah Fish, Gabrielle Blanco et autres

Supplementary Table S1 shows CRISPR screen hits