Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities.
10 affiliations
- 1Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
- 2Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- 3Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- 4Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- 5Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- 6The ChemoGenix CRISPR Screening Platform of the Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, H3T 1J4, Canada.
- 7Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA. [email protected].
- 8Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, 68198, USA. [email protected].
- 9Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA. [email protected].
- 10Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA. [email protected].
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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BibTeX
@article{umeta2026chemical,
title = {{Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities.}},
author = {Lelisse T Umeta and Jayapal Reddy Mallareddy and Sarbjit Singh and Karan Vishwakarma and Smitha Kizhake and Wangbin Wu and Amritha G Kizhake and Lidia Boghean and Suchita Vishwakarma and Mihir Kachhia and A J Sallee and Vaishnavi Sunil Joshi and Katelyn L O'Neill and Lisa Humphrey-Brattain and Linda Chee and Matthew G Rees and Melissa M Ronan and Jennifer A Roth and Andrew Chatr-Aryamontri and Thierry Bertomeu and Kabhilan Mohan and Yuanhong Chen and Kyle Hewitt and Grinu Mathew and Adrian Black and Gargi Ghosal and Xu Luo and Jixin Dong and Nicholas T Woods and Amarnath Natarajan},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00632-z},
url = {https://europepmc.org/article/MED/42955492},
note = {CC BY},
}
RIS
TY - JOUR
TI - Chemical genetic screens combine target dependence with efficacy: discovery of a MAP3K1 degrader (HBC-8) with anticancer activities.
AU - Lelisse T Umeta
AU - Jayapal Reddy Mallareddy
AU - Sarbjit Singh
AU - Karan Vishwakarma
AU - Smitha Kizhake
AU - Wangbin Wu
AU - Amritha G Kizhake
AU - Lidia Boghean
AU - Suchita Vishwakarma
AU - Mihir Kachhia
AU - A J Sallee
AU - Vaishnavi Sunil Joshi
AU - Katelyn L O'Neill
AU - Lisa Humphrey-Brattain
AU - Linda Chee
AU - Matthew G Rees
AU - Melissa M Ronan
AU - Jennifer A Roth
AU - Andrew Chatr-Aryamontri
AU - Thierry Bertomeu
AU - Kabhilan Mohan
AU - Yuanhong Chen
AU - Kyle Hewitt
AU - Grinu Mathew
AU - Adrian Black
AU - Gargi Ghosal
AU - Xu Luo
AU - Jixin Dong
AU - Nicholas T Woods
AU - Amarnath Natarajan
PY - 2026
DA - 2026/10/28
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00632-z
UR - https://europepmc.org/article/MED/42955492
AB - 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.
SN - 2662-8651
ER -