# The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $378,504

## Abstract

Project Summary
Developed in the 1950s, Thalidomide was used to treat morning sickness in the early stages of pregnancy, which
led to the birth of thousands of children with severe birth defects and subsequent withdrawal from the market.
Today, thalidomide and its analogs lenalidomide and pomalidomide (collectively known as IMiDs) are FDA
approved drugs and effective treatments for hematologic malignancies such as multiple myeloma and Del(5q)
MDS. But despite over 60 years of research, the mechanistic understanding of how these molecules cause the
characteristic birth defects is only just beginning to unravel. Due to the wide use of IMiDs in the clinic, and the
recent explosion in the development of targeted protein degradation therapies based often on the original
thalidomide scaffold, it is more critical than ever that we understand the full range of potential activities that IMiDs
provoke. Here, we propose to explore the broad range of potential activities that result from these IMiD-like
molecules binding to the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) and redirecting its activity towards
different targets. Specifically, in aim 1, we will engineer an in vivo mouse model of Sall4 degradation to dissect
how thalidomide-mediated degradation of Sall4 leads to teratogenicity. We will do this through a combination of
expression analyses and developmental measurements to assess the affect that IMiD molecules have on the
developing embryo. This will not only enable the study of the mechanism of teratogenic activity of these drugs
but will also provide a critical model system for testing the toxicity of current and future versions of these
molecules. Not only do these molecules induce a gain-of-function to target new proteins, but they also induce a
loss-of-function and in aim 2, we propose to use novel mass spectrometry-based proteomics technology in
combination with potent and selective tool compounds to explore the biological consequences of blocking CRBN
activity. We have previously shown that we can expand the scope of IMiD targets through rational design of new
IMiD-like molecules capable of degrading new proteins related to known targets. In aim 3, we propose to expand
the target scope even further by developing novel chemistry to target structurally diverse proteins that have a
strong therapeutic rationale, thus providing proof-of-concept for target expansion and providing chemical leads
for new therapeutic targets. The overarching goal of this grant is to explore the full range of potential activities of
the widely utilized CRL4CRBN ligase by identifying and exploring the mechanistic consequences of degrading its
physiological and IMiD-induced targets, as well as seeking to expand its target space into currently undruggable
territories.

## Key facts

- **NIH application ID:** 10888990
- **Project number:** 5R01CA214608-08
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Eric Sebastian Fischer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,504
- **Award type:** 5
- **Project period:** 2017-03-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888990

## Citation

> US National Institutes of Health, RePORTER application 10888990, The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase (5R01CA214608-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10888990. Licensed CC0.

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