Identification of small molecule inhibitors against doublecortin-like kinase 1 for targeting colon cancer stem cells

Abstract

As per the World Health Organisation (WHO) reports, colon cancer ranks second among cancer types affecting women,
and third among those affecting men. An evolving hypothesis in the field of oncogenesis posits that a limited population of
quiescent cells can give rise to primary tumors. The investigation of cancer stem cells (CSCs) offers a potential avenue for
devising innovative approaches to cancer therapy. Notably, the identification of doublecortin-like kinase 1 (DCLK1) assumes
significance as it serves as a distinctive marker for CSCs in pancreatic and colon cancer contexts. Nevertheless, the clinical
translation of silencing DCLK1 via small interfering RNA (siRNA) encounters various pragmatic impediments. Consequently,
the pursuit of specific inhibitors targeting DCLK1 emerges as a promising strategy for impeding the processes of cancer
initiation, progression, and metastasis, partly by modulating epithelial-mesenchymal transition (EMT) and inducing CSC
apoptosis. In this study, our investigation involved querying a repository of traditional Chinese medicinal compounds to discern
potential small molecules exhibiting affinity for DCLK1. The compound that displayed the most favorable attributes, luteolin,
was subsequently subjected to molecular dynamics simulations. Our computational analysis unveiled luteolin's remarkable
qualities, characterized by its conspicuously low binding energy and heightened affinity for the DCLK1 protein. Notably, the
simulation divulged a sustained and intricate binding interaction between luteolin and the DCLK1 protein, involving a range of
one to four hydrogen bonds throughout the simulation's 100 nanoseconds trajectory. Furthermore, the minimal root mean square deviation observed throughout the simulation duration indicates the stability of the DCLK1-luteolin complex. The identification and validation of distinct inhibitors targeting DCLK1 possess the potential to transform extant approaches to cancer treatment. By exerting control over EMT and instigating the death of CSCs, these inhibitors could aid in transformative changes in the landscape of cancer therapy strategies.