Abstract 1727: Development of novel TAK1 inhibitors for pancreatic cancer

Abstract

Abstract Transforming growth factor- (TGF-) activation kinase (TAK1, MAP3K7) is a member of MAPKKK family [1]. It was well established that TAK1 plays a key role in both TNFα and IL-1 pathway. Knock down of TAK1 impaired the activation of IKK and JNK by TNFα and IL-1 [2, 3]. NF-B activation induced by TNFα and IL-1 are severely impaired in TAK1 knock out MEF cells [4]. TAK1 acts as the kinase of IKK and therefore regulates NF-κB activation. Our previous work has demonstrated that TAK1 is upregulated and plays an important role in chemotherapeutic drug resistance in pancreatic cancer cells. Block TAK1 activity can reverse pancreatic cancer cell resistance to chemotherapeutic drug and reduce tumor size in Orthotopic Xenograft models [5]. These findings underscore the significance of TAK1 in mediating drug resistance. Strategies to target TAK1 may play a critical role in the treatment of this deadly malignancy. Utilizing computational-based structural modeling and a recently published crystal structure of TAK1, compounds were designed to inhibit the ATP-binding pocket of the TAK1. Synthetic templates were proposed for building a urea based library of potential inhibitors. A multiple stage docking involving both pre- and post-filtering and progressively more stringent docking criteria led to approximately 1,000 structures. The resulting scores from two docking programs were fed into workflow software that combined the results and calculated ADME properties. To provide better consistency in scoring and less bias in setting the filtering cutoffs, we also included docking decoys and utilized a more statistically relevant Z-score. After application of a final binding mode filter, there were 22 structures that were selected and ranked. A seven-step synthesis was developed and a focused library of compounds was synthesized from those top-ranked compounds. Note: This abstract was not presented at the meeting. Citation Format: Paul J. Chiao, Zhuonan Zhuang, Qianghua Xia, Paul T. Schuber, Duoli Sun, Zhenghong Peng, David S. Maxwell, William G. Bornmann. Development of novel TAK1 inhibitors for pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1727. doi:10.1158/1538-7445.AM2014-1727