# Degrading therapeutically important kinases using small molecules

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $650,235

## Abstract

Targeting of oncogenic kinases with small molecule inhibitors is now a well validated paradigm for treatment of
cancer types and approximately 25 drugs directed at targets such as ALK, EGFR, BCR-ABL, BTK, C-KIT, b-
RAF and PDFGRβ are now in routine clinical use. Unfortunately, except for long-term responses to BCR-ABL
inhibitors in Chronic Myeloid Leukemia, resistance to other inhibitors typically develops 1-2 years after an
initially successful response. In addition, some tumors depend on the scaffolding function of a kinase and not
on enzymatic kinase activity, thereby rendering inhibitors ineffective. For example the pseudokinase Her3 is an
obligate heterodimerization partner with EGFR and Her2 but its kinase activity is not required. Here we
propose to explore a fundamentally new approach to abrogating kinase function using small
molecules that can selectively promote the degradation of kinase targets of interest. In particular, we will
exploit a recently described approach involving the development of bivalent small molecules that induce
ubiquitination and subsequent proteasomal degradation of targets of interest. We will use ligands related to
thalidomide, which can recruit the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) that we call `selective
degraders' (also known as PROTACs or degronimids). We have developed a powerful mass spectrometry-
based proteomics approach that has allowed us to determine which kinases are more susceptible to
degradation by this strategy, which has identified two well credentialed targets that are very efficiently
degraded: BTK and FLT3. We have developed excellent prototype degraders for FLT3 and BTK which will be
further optimized to obtain compounds capable of degrading these targets in vivo. In addition, we have
identified a target of therapeutic interest, HER3 that is a pseudokinase (catalytically inactive) but serves as a
critical dimerization partner with EGFR and HER2 and therefore represents a unique opportunity for targeting
through degradation. The goal of this grant application is to develop optimized small molecule
degraders of BTK, FLT3 and HER3 and to understand the biochemical and structural underpinnings of
their mechanism of action. Well validated cellular models that exhibit dependencies on these kinases, will be
used to investigate how the cellular response differs between kinase inhibition and degradation.!

## Key facts

- **NIH application ID:** 9830608
- **Project number:** 5R01CA218278-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Eric Sebastian Fischer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,235
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830608

## Citation

> US National Institutes of Health, RePORTER application 9830608, Degrading therapeutically important kinases using small molecules (5R01CA218278-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830608. Licensed CC0.

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