# Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities

> **NIH NIH R35** · YALE UNIVERSITY · 2024 · $915,360

## Abstract

The pharmaceutical industry is in a crisis; unfortunately the post-genomic era has not significantly changed
the number of proteins pursued by drug companies. This dearth of new cancer drug targets has resulted
in too many ‘me too’ drugs and wasted effort. To address this need, my lab has focused on developing
the new field of ‘Controlled Proteostasis’. Our initial efforts focused on inhibiting protein turnover; we
developed a novel proteasome inhibitor, YU101, which served as the basis of a new oncology-based
biopharma, Proteolix, Inc. from my lab. Ultimately, YU101 became carfilzomib/Kyprolis®, which was
approved by the FDA in 2012 for relapsed/refractory multiple myeloma. More recently, my lab has been
focused on the flipside of protein turnover, i.e., developing a small molecule analogy to siRNA to induce
protein knockdown. We have shown that this strategy, known as Proteolysis Targeting Chimerae
(PROTACs) can effectively recruit targeted oncoproteins to E3 ubiquitin ligases for induced degradation,
both in cell culture and in vivo. Over the past six years of the current R35, I have worked closely with
another biopharma that I founded, Arvinas, Inc., to apply this approach to nuclear hormone receptors in
oncology. Arvinas’ two PROTAC-based drug candidates (targeting AR and ER, for prostate and breast
cancers, respectively) have been shown to decrease their target proteins in first-in-human clinical trials,
thus validating our PROTAC technology. In the next R35 phase, I propose to develop this technology
further through the identification of key degradable oncogenic driver proteins and through the development
of tumor-selective PROTACs. Moreover, the clinical validation of PROTACs supports the development of
additional novel therapeutic modalities based on heterobifunctional compounds that co-opt various
intracellular machineries. These innovative approaches have the potential to be new drug development
paradigms that could have a significant impact by dramatically expanding the protein classes one can
target pharmaceutically. Finally, for the past 26 years, I have focused on translating research from my lab
into both new oncology-focused ventures and a FDA-approved drug, thus demonstrating truly ‘bench-to-
bedside’ research that is not common in academia today. This track record of innovation and execution
within translational cancer research are strong predictors of continued future success.

## Key facts

- **NIH application ID:** 10898855
- **Project number:** 5R35CA197589-10
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CRAIG M CREWS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $915,360
- **Award type:** 5
- **Project period:** 2015-09-09 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898855

## Citation

> US National Institutes of Health, RePORTER application 10898855, Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities (5R35CA197589-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898855. Licensed CC0.

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