Chemical-Induced Proximity for Control of STAT Transcription Factor Networks

ASPIRE Award (2023-Present)

Courtney Hodges, PhD; Damian Young, PhD, Baylor College of Medicine, Nate Hathaway, PhD, University of North Carolina

Courtney Hodges, PhD

Damian Young, PhD

Nate Hathaway, PhD

Transcription factors (TFs) are a class of proteins that play a crucial role in controlling gene expression by directly binding to specific DNA sequences. Mutations, amplifications, fusions, and deletions of transcription factors have been implicated in the initiation and progression of cancer, making them attractive targets for new cancer therapeutics. However, drugging transcription factors has proven challenging due to their lack of naturally occurring small molecule binding sites and the difficulty in achieving the desired functional output even if a binding site is identified. In recent years, researchers have revisited this problem by exploring induced proximity strategies, particularly in the context of Proteolysis targeting chimeras (PROTACs), which lead to degradation of target proteins. However, the limitation of near-total loss-of-function associated with targeted protein degradation has become apparent, as PROTACs only allow for loss-of-function modulation and do not provide a means to enhance desirable TF activity.

In a previous ASPIRE award, Courtney Hodges, Nate Hathaway, and Damian Young successfully validated an induced proximity-based approach to modulate the activity of STAT1, an important transcription factor involved in immune signaling. By engineering induced proximity with the transcriptional regulator BRD4, they demonstrated the vulnerability of acute myeloid leukemia (AML) cells through modulation of STAT1 activity across the genome. Building on this success, their current goal is to develop small-molecule binders specifically targeting STAT1. To achieve this, they will validate and characterize hits from a DNA-encoded library chemical screen previously performed to target STAT1. Selective STAT1 binders will be linked to different warheads to assess the activity of such bifunctional molecules in an AML cell line. Leveraging their expertise in chromatin biology, medicinal chemistry, and chemical biology, the investigators intend to enable the development of a novel class of small molecules that act through induced proximity of STAT1 with chromatin regulators. This approach aims to tap into the complex biological regulation associated with transcription factors, providing new opportunities for therapeutic intervention.