Abstract Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase that plays a critical role in the maintenance of gastrointestinal (GI) epithelial integrity and regeneration. Emerging evidence highlights the functional divergence of its isoforms—particularly the long and short forms—which are differentially expressed during homeostasis and disease. In healthy GI tissue, DCLK1-long primarily maintains stem cell quiescence and epithelial repair. Conversely, DCLK1-short is markedly elevated in several GI malignancies and is associated with oncogenic transformation, invasion, and poor prognosis. We are investigating compounds that modulate DCLK1 isoforms to mitigate irradiation-induced gastrointestinal acute radiation syndrome (GI-ARS). Our research demonstrates that 2-deoxyglucose (2DG) and its non-metabolizable analogue differentially regulate crypt and colonoid growth in ex vivo systems. Treatment with 2DG results in selective suppression of the DCLK1-short isoform while sparing or modestly enhancing the DCLK1-long variant, suggesting a potential therapeutic window for targeting tumor-specific isoform expression. To further identify molecular binders capable of modulating DCLK1 activity, we employed a structure-based virtual screening approach using a focused library of 100,000 small molecules. High-throughput in silico docking enabled the identification of several high-affinity lead compounds with potential isoform-selective binding. The strategy of small-molecule screening offers a promising approach for selective intervention in DCLK1-driven pathologies in GI tissue repair. Citation Format: Uzma Uzmi, Shahid Umar, Prashanthi Karyala, Rao VL Papineni. Novel selective binders for gastrointestinal DCLK1 isoforms abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6622.
Uzmi et al. (Fri,) studied this question.