Abstract A20: Small-molecule (LWKS22) drug discovery for pancreatic cancer therapy.

Abstract

Pancreatic cancers respond poorly to chemotherapy, more effective and less toxic treatment is a crucial need. We have employed a biological assay (MTS assay) to identify small molecule compounds that induce cytotoxicity specifically in pancreatic cancer cells and not in normal cells by screening large number of compounds from combinatorial chemistry library. One of the compounds, LWKS22 (MW: 547.94) kills pancreatic cancer cells and not the normal pancreatic cells (h-tert HPNE). LWKS22 kills pancreatic cancer cells isolated from all the four stages and the EC50 is in the range of 2-10 μM, whereas for normal cells is 70 μM. Maximum tolerated dose is 80 mg/kg of body weight. At 20 mg/Kg body weight, it showed significant tumor shrinkage in human PDAC xenografts mice model when compared to PBS controls. Hypothesis and Specific Aims: The structure activity relationship studies of LWKS22 revealed that the parent compound structure is very important for its killing activity. LWKS22 was submitted to National drug therapeutics center, NIH, to screen for 60 different cancer cells derived from various human cancers. LWKS22 showed significant killing in human colon cancer cells and lymphoma cells, suggesting that this compound specifically targets some oncoproteins that are expressed in these cancer types. Now, the therapeutic potential of LWKS22 is confirmed. Identification of LWKS22 binding partner and its signaling mechanism to kill PDAC cancer cells will certainly add more benefits for the pancreatic cancer therapy. We hypothesize that LWKS22 can be developed as a therapeutic agent against pancreatic cancer along with other chemotherapy. To make it is a therapeutic agent, its mechanism of action, targeting receptors, signaling pathway, biodistribution and pharmacokinetics studies need to be conducted. Experimental Design: Therapeutic efficacy of LWKS22 was evaluated with mice bearing PDAC primary tumors. Photoaffinity labeling, chemoaffinity labeling methods and molecular biology techniques will be used to identify LWKS22’s binding partners. Impact: We have identified a compound that will kill cancer cells and not the normal cell. Targeting more than one pathway is one of the best ways to control this lethal disease. Functional characterization of this LWKS22 will certainly add more benefits for pancreatic cancer therapy. Citation Format: Yan Wang, Angela Echaverri, Anastasia Warde, Thiru Arumugham, Kit Lam, Pappanaicken Kumaresan. Small-molecule (LWKS22) drug discovery for pancreatic cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A20.