Pharmacologically modulating transcriptional regulators of immune cells:
Transcription factors are key regulators of proper immune cell phenotypes but also drive immune dysfunction in the setting of cancer. However, transcription factors have largely been studied through genetic gain- or loss-of-function approaches, and the effects of acute activation or inhibition is not clear, nor is whether they may be tractable drug targets. We will employ chemical biology techniques to dissect the effects of pharmacological modulation of transcription factors on immune cell phenotype and function.
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Enhancing tumor cell immunogenicity:
The impressive clinical advances engendered by immunotherapies have revolutionized cancer therapy, but only a subset of patients benefits from these treatments, so dissecting and targeting the mechanisms that contribute to antigen presentation or immune evasion by tumor cells may lead to enhanced efficacy. We will employ both targeted approaches for known immunoregulatory genes and unbiased small molecule screens to identify and modulate the pathways underpinning tumor immune evasion.
Expanding the druggable proteome:
While the majority of the proteome, particularly transcription factors, has not been druggable, emerging chemical biology approaches can expand the scope of accessible proteins. For example, small molecule degraders, by virtue of their ability to induce interactions between E3 ligases and neosubstrates, can broaden the spectrum of druggable proteins. In collaboration with medicinal chemists, we will develop and characterize novel chemical probes of previously undruggable proteins.
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