Event Abstract Back to Event Exploring the potential of andrographolide and its derivatives as anti-pancreatic cancer therapeutics: in silico, in vitro, and in vivo approaches Shun Ying Quah1, Kok Lian Ho1, Nizar Abdul Manan1, Sreenivasa R. Sagineedu2, Pran Kishore Deb3 and Johnson Stanslas1* 1 Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia 2 International Medical University, Malaysia 3 Philadelphia University, Jordan Background Approximately 95% of pancreatic ductal adenocarcinoma (PDAC) patients are found having oncogenic K-Ras, which perturbs mitogen-activated protein kinase (MAPK) cascade critical for cellular processes. Our previous analysis identified andrographolide (AGP) derivatives, SRJ09 and SRJ23, disrupted MAPK activation by binding to K-Ras. Chemical modification of SRJ23 produced S8, which selectively inhibited PDAC cell growth. This study aims to evaluate these compounds computationally on K-Ras, and their in vitro and in vivo anticancer activity against PDAC. Methods Using Glide (Schrödinger, LLC), molecular docking was performed to identify the binding mode and affinity of AGP and its analogues to wild-type and mutant K-Ras. PANC-1 cells harbouring K-RasG12D, the most predominant K-Ras mutation, were used in cell-based and animal studies. Soft-agar colony formation assay was performed to determine the ability of compounds to inhibit anchorage-independent cell growth. GTP-loading of K-Ras and MAPK activation were assessed by immunoblotting. Anti-tumour activity was assessed in athymic nude mice carrying PANC-1 tumour xenografts. Tumour tissues were evaluated histologically by haematoxylin-eosin staining. Results S8 bound stronger to K-Ras mutants, specifically K-RasG12D and K-RasG12V (-76.54kcal/mol and -80.43kcal/mol, respectively, versus -69.40kcal/mol in wild-type K-Ras). Contrary to AGP and SRJ09, SRJ23 and S8 anchored into a binding pocket located between two switches of K-RasG12V, via their lactone ring, where the 14-OH group interacted with aspartate-54 through hydrogen-bonding. SRJ23 and S8 comparably inhibited PANC-1 colony formation in a dose-dependent manner. However, S8 produced greater repression in GTP-loading of K-Ras and suppressed Erk phosphorylation in PANC-1 cells. S8 significantly decelerated tumour growth in PANC-1-xenografted nude mice at a dose of 100mg/kg, and caused a higher degree of tumour necrosis, in comparison to SRJ23 treatment at the same dose. Conclusion S8 likely binds to oncogenic K-Ras, leading to inhibition of the aberrant Ras-MAPK signalling and reduction in pancreatic tumourigenesis in vitro and in vivo. Keywords: PDAC, MAPK, tumourigenesis, Andrographolide derivatives, Oncogenic K-Ras Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Oral Presentation Topic: Cancer Citation: Quah S, Ho K, Abdul Manan N, Sagineedu SR, Deb P and Stanslas J (2019). Exploring the potential of andrographolide and its derivatives as anti-pancreatic cancer therapeutics: in silico, in vitro, and in vivo approaches. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00022 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2018; Published Online: 17 Jan 2019. * Correspondence: Prof. Johnson Stanslas, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia, rcxjs@upm.edu.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Shun Ying Quah Kok Lian Ho Nizar Abdul Manan Sreenivasa R Sagineedu Pran Kishore Deb Johnson Stanslas Google Shun Ying Quah Kok Lian Ho Nizar Abdul Manan Sreenivasa R Sagineedu Pran Kishore Deb Johnson Stanslas Google Scholar Shun Ying Quah Kok Lian Ho Nizar Abdul Manan Sreenivasa R Sagineedu Pran Kishore Deb Johnson Stanslas PubMed Shun Ying Quah Kok Lian Ho Nizar Abdul Manan Sreenivasa R Sagineedu Pran Kishore Deb Johnson Stanslas Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.