Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities

Abstract Heterobifunctional compounds (HBCs) that facilitate target protein degradation (TPD) by recruiting an E3 ligase complex have emerged as therapeutic options for cancer. Current screening approaches often prioritize protein degradation over anticancer activity, potentially missing therapeutically relevant compounds. To address this, we developed a viability-based screening strategy using isogenic wild-type, MAP3K1 -knockout, and CRBN -knockout cell lines to identify HBCs with target- and E3-ligase-dependent anticancer effects. This approach identified HBC-8, which is > 30-fold more potent than the parent MAP3K1 inhibitor and induces S-phase arrest, growth inhibition, and apoptosis in a MAP3K1- and CRBN-dependent manner. HBC-8 degrades MAP3K1; however, proteome-wide, genome-wide, and large-scale viability-based screens indicate that the anticancer activity of HBC-8 also relies on the disruption of the ubiquitin–proteasome system and protein translation machinery, extending beyond MAP3K1 degradation alone. Target dependence of HBC-8 was established using a large-scale viability screen in 869 cancer cell lines, and the anticancer effects correlated with the expression levels of the target (MAP3K1) and E3 ligase (CRBN). Furthermore, HBC-8 showed antitumor effects in an in vivo orthotopic ovarian cancer model without observable toxicity, supporting the use of isogenic cell lines for chemical genetic screens as a rapid, holistic approach to identify therapeutically relevant HBCs that also degrade the target protein.

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Publication Details

Journal
Molecular Biomedicine
Published
2026-10-28
DOI
https://doi.org/10.1186/s43556-026-00632-z
Primary Topic
Protein Degradation and Inhibitors
Type
article
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article

Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities

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Molecular Biomedicine
Protein Degradation and Inhibitors
article

Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities

Melissa M. Ronan, Jayapal Reddy Mallareddy, Jixin Dong, Amarnath Natarajan, Gargi Ghosal, Thierry Bertomeu, Mihir Kachhia, Smitha Kizhake, Jennifer A. Roth, Karan Vishwakarma, Katelyn L. O’Neill, Matthew G. Rees, Lidia Boghean, Grinu Mathew, Wangbin Wu, Kyle J. Hewitt, Nicholas T. Woods, Lelisse T. Umeta, Andrew Chatr‐aryamontri, Amritha G. Kizhake, Sarbjit Singh, Xu Luo, Kabhilan Mohan, Linda Chee, Lisa Humphrey-Brattain, Adrian Black, Vaishnavi Sunil Joshi, A. J. Sallee, Suchita Vishwakarma, Yuanhong Chen
article en

Abstract

Abstract Heterobifunctional compounds (HBCs) that facilitate target protein degradation (TPD) by recruiting an E3 ligase complex have emerged as therapeutic options for cancer. Current screening approaches often prioritize protein degradation over anticancer activity, potentially missing therapeutically relevant compounds. To address this, we developed a viability-based screening strategy using isogenic wild-type, MAP3K1 -knockout, and CRBN -knockout cell lines to identify HBCs with target- and E3-ligase-dependent anticancer effects. This approach identified HBC-8, which is > 30-fold more potent than the parent MAP3K1 inhibitor and induces S-phase arrest, growth inhibition, and apoptosis in a MAP3K1- and CRBN-dependent manner. HBC-8 degrades MAP3K1; however, proteome-wide, genome-wide, and large-scale viability-based screens indicate that the anticancer activity of HBC-8 also relies on the disruption of the ubiquitin–proteasome system and protein translation machinery, extending beyond MAP3K1 degradation alone. Target dependence of HBC-8 was established using a large-scale viability screen in 869 cancer cell lines, and the anticancer effects correlated with the expression levels of the target (MAP3K1) and E3 ligase (CRBN). Furthermore, HBC-8 showed antitumor effects in an in vivo orthotopic ovarian cancer model without observable toxicity, supporting the use of isogenic cell lines for chemical genetic screens as a rapid, holistic approach to identify therapeutically relevant HBCs that also degrade the target protein.

Molecular BiomedicineVol. 7(1)
Broad Institute (US), Institute for Research in Immunology and Cancer (CA), University of Nebraska Medical Center (US), University of Cincinnati (US), Université de Montréal (CA)
Openalex Percentile: Top 22%
Protein Degradation and Inhibitors
DOIOpen Access PDFOpenAlex
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