Targeting Doublecortin‐like Kinase 1 (DCLK1) in Colon Cancer: An In‐silico Approach

Abstract

Cancer stem cells (CSCs) are proposed to be a contributing factor in colorectal cancer (CRC) recurrence and chemo‐resistance, as a result of increased expression of ABC transporters and their innate ability to self‐renew and enter a quiescent state. Current standard therapies are ineffective at eliminating these CSC populations, hence there is a need to identify novel agents to effectively inhibit their growth. Multiple surface markers have been identified for CRC‐CSCs, though few have shown promise as a clinical target. Recently, doublecortin‐like kinase 1 (DCLK1) was established as a CSC marker in CRC and pancreatic cancers. The N‐terminal doublecortin domains(DCX) bind microtubules and regulate their polymerization, while the C‐terminal serine/threonine‐protein kinase domain is involved in cellular signaling. DCLK1 is a marker of Tuft cells in normal intestinal crypts, but in cancer is found to be highly expressed in CSC populations that play a critical role in tumor progression, based on lineage tracing experiments. Specific ablation of DCLK1+ stem cells causes marked regression of polyps without apparent damage to the normal intestine, distinguishing DCLK1 as a CSC marker. Recently, marmelin, a phytochemical from Aegle marmelos, has been shown to target DCLK1 and reduce CRC tumor growth in vivo. Hence, DCLK1 represents an attractive target for CSC‐targeted drug discovery. The present study is aimed to identify small molecule inhibitors of DCLK by using in silico molecular docking‐based screening. For this, we tested a library of FDA‐approved drugs and kinase inhibitors using Autodock Vina software. Compounds were assessed on their ability to bind within the ligand binding site of the C‐terminal kinase domain. The compounds are ranked‐based on their binding energies and hydrogen bonding patterns.Support or Funding InformationThe Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine the structure‐function relationship in this project.