VCOM Louisiana Research Day Program Book 2024

Biomedical Research: Section 2

Ali Gholamian Moghaddam 1 ; Atchimnaidu Siriki 1 ; Debajyoti Majumdar 3 ; Hassan Y Ebrahim, PhD 3 ; Khalid El Sayed 2 ; Seetharama Jois 3 ; Siva Murru 1 1 School of Sciences, College of Arts, Education and Sciences, ULM; 2 Basic Pharmaceutical and Toxicological Sciences, ULM College of Pharmacy; 3 Department of Pathobiological Sciences, LSU School of Veterinary Medicine 23 DEVELOPMENT AND EVALUATION OF NOVEL AZOLE COMPOUNDS FOR ANTI-CANCER ACTIVITY: IN SILICO AND IN VITRO ANALYSIS TARGETING TTK AND AURK DUAL INHIBITION

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women in the United States. Existing cancer treatments encounter hurdles such as unsustainable clinical effectiveness and acquired drug resistance. Consequently, extensive efforts are underway to discover potent anti-cancer agents that exhibit greater selectivity and reduced toxicity. Notably, many tyrosine and serine/threonine protein kinase families are implicated in the initiation and progression of human cancer. TTK and Aurora kinase B in cancer target therapy have garnered significant attention due to their implications in cell cycle regulation and chromosomal segregation. TTK plays a crucial role in ensuring proper chromosome alignment and segregation during mitosis. Dysregulation of TTK has been associated with chromosomal instability, a hallmark of cancer. In cancer target therapy, inhibition of TTK has shown promise in disrupting mitotic progression, leading to mitotic catastrophe and cell death, particularly in cancer cells with inherent chromosomal instability. Aurora kinase B, a key regulator of cytokinesis and chromosomal segregation, is another vital player in cancer target therapy. Its overexpression has been observed in various

malignancies, contributing to abnormal cell division and genomic instability. Objective: Kinases have been studied as potential drug targets for anticancer drug development. The development of small molecule Tyrosine Kinase Inhibitors (TKIs) and Serine/Threonine Kinase Inhibitors (STKIs) has gained recent interest in targeted cancer therapy by selectively inhibiting related Kinases. These therapies have significant advantages over traditional chemotherapy in that they target specific proteins that are known to have important roles in tumor growth and progression. Numerous pyrazole derivatives have emerged as promising candidates in the realm of anticancer therapeutics, demonstrating robust efficacy through their ability to inhibit tyrosine and serine/ threonine kinases. Among the diverse array of tyrosine and serine/threonine kinases involved in targeted cancer therapy, MPS1 kinase and Aurora Kinase B play pivotal roles in regulating cell division and maintaining genomic stability. MPS1 kinase is a key regulator of the mitotic checkpoint, ensuring proper chromosomal alignment and segregation during cell division. On the other hand, Aurora Kinase B is essential for cytokinesis and proper formation of the mitotic spindle. Its aberrant activity has been linked to chromosomal instability and tumor

progression. The development of small-molecule inhibitors targeting MPS1 kinase and Aurora Kinase B has shown promise in disrupting these critical pathways, offering new avenues for precision anticancer therapies. Methods: Our lab achieved the successful development of Suzuki-coupling reactions using a microwave synthesizer, leading to the synthesis of a diverse array of small-molecule compounds. We subjected all synthesized compounds to MTT assays against colorectal cancer cell lines, such as Widr and HCT-116, revealing a selection of potent compounds exhibiting favorable IC50 values. Furthermore, the kinase profiling experiments conducted on the highly potent compounds revealed substantial inhibition of TTK and Aurora kinases. To confirm these findings, we performed molecular docking studies on potent pyrazolone compounds and their analogs, targeting the protein structures of TTK and Aurora Kinase B. Additionally, we chose the most powerful compound from our selection to assess its colony-forming inhibitory potential and anti metastatic activity through colony-formation and wound healing assays. Additionally, we have performed ADME predictions using SwissADME software to evaluate the drug potential of the synthesized compounds, considering

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