Research
The overarching goal of the Nabet lab is to advance innovative therapeutic modalities and treatment paradigms for patients with difficult-to-treat cancers.
We aim to do so by developing and deploying novel chemical biology strategies to inhibit, degrade, or activate clinically relevant targets within oncogenic signaling networks. We pioneered a technology known as the degradation tag (dTAG) system that employs small molecule degraders to harness the cell’s ubiquitin-proteasome machinery to eliminate tagged proteins with speed and precision. We leverage dTAG and develop novel proximity-inducing technologies to discover, validate, and gain new insights into oncogenic signaling networks.
We believe in open-source team science and collaborate with medicinal chemists, biochemists, and cancer biologists worldwide to deliver new solutions for cancers that currently resist therapies. Through these efforts we work to deepen our biological understanding of the molecular circuits that drive cancer cell survival and growth as well as translate these insights into therapeutic strategies for unmet medical needs.
Our current research is focused on:
Targeting vulnerabilities that coordinate resistance to signaling disruption in cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human cancers, and the development of targeted therapeutics for oncogenic drivers of PDAC has been difficult to achieve. While directly targeting mutant KRAS is a major research focus, intrinsic and acquired resistance emerges in response to mutant KRAS inhibition or loss. We employ the dTAG system to define the transcriptional regulators responsible for adaptive survival to disruption of KRAS signaling and aim to identify combination approaches targeting these factors to improve the durability of responses in PDAC.
Evaluating the clinical potential of targeted degradation as a therapeutic strategy in cancer.
Targeted protein degradation is a breakthrough approach, whereby proteins are pharmacologically eliminated through the proteasome rather than inhibited. To leverage the advantage of degraders for eliminating all protein function, we employ the dTAG system for target discovery and validation and collaborate with medicinal chemists to develop direct-acting small molecule degraders for therapeutic targets with enzymatic and non-enzymatic activities. We aim to characterize small molecule degraders in translationally relevant cancer models to gain new insights into the biological activities of targeted proteins and to provide a framework for preclinical evaluation of targeted disruption of these factors.
Developing next-generation strategies to control target protein activity.
Developing strategies to activate target proteins such as tumor suppressors using pharmacological approaches has been a major challenge. We focus on developing novel technologies for protein stabilization through recruitment of enzymes capable of inducing post-translational modifications of target proteins that increase their stability and half-life. We aim to expand the spectrum of proximity-induced interactions that can modulate protein activity for therapeutic gain.
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