QSAR and Anticancer Drug Design on Benzothienopyrimidinones as Promising Pim Kinase Inhibitors Utilizing Structural Descriptors

Introduction

Cancer is characterized by abnormal growth and division of cells, which are collectively termed as malignancies. Abnormal mitotic cell cycle leads to malignancies. Signal transduction through various kinases plays a great role in mitotic cell division (Hartwell and Kastan, 1998). Over expression of these kinases, it may produce abnormal cell division. Therefore, inhibition of abnormal expression of such kinases including Pim (Pro-viral Insertion in Murine leukemia virus) is one of the major strategies for anticancer drug development. Pim was represented as Pro-viral Insertion in Murine leukemia virus, which is a proto-oncogene formerly discovered in mouse models in 1980. They are classified into Pim-1, Pim-2, and Pim-3, which encode a family of three constitutively active serine/threonine/tyrosine kinases. Pim kinases are apoptotic inhibitors and positive regulators of G₁-S and G₂-M phase progression of the mitotic cell cycle. Pim-1 and Pim-2 have been found to be overexpressed in solid tumors including prostate, pancreatic and colon cancer and other human hematopoietic malignancies such as leukemia and lymphoma including chronic lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma (Dhanasekaran et al., 2001; Valdman et al., 2004; Xu et al., 2005; Kim et al., 2005; Pasqualucci 2001). Pim kinases are involved in the phosphorylation of components of the targets that play a role in many cellular processes such as transcription, translation, survival, cell cycle, signal transduction, and migration (Bachmann and Moroy 2005; Wang et al., 2001). Pim-3 is overexpressed in human hepatoma cell lines HepG2 and hepatocellular carcinoma. More recently, Pim-3 has been observed to be abnormally expressed in human colon and pancreatic cancers and to phosphorylate Bcl-2-associated death promoter (Bad), thereby blocking Bad-mediated apoptosis (Fuji et al.2005). Therefore, a number of attempts have been made to develop small molecule Pim kinase inhibitors to be effective against cancer. Several non-selective Pim kinase inhibitors including CX-6258 (Haddach et al., 2012), AZD1208 (Kreuz et al., 2015), 1,10-dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde (DHPCC-9) (Santio et al., 2010), SGI-1776(Cervantes-Gomez et al., 2013)and Thienopyrimidines were being studied under clinical investigation (Jennings et al., 2005). El-Baih and co-workers synthesized a number of thioxothienopyrimidinones, alkylthio- and arylalkylthiothienopyrimidinones, thienopyrimidinones, thienopyrimidines a thienopyrimidinedione and a thienotriazolopyrimidinone which were prepared from 2-amino-3-carboethoxy-4,5-disubstituted thiophenes and 2-amino-3-cyano-4,5-disubstituted thiophenes via reactions with different reagents (Fatma et al., 2006). Interestingly, tricyclic benzothienopyrimidinones constitute a new class of Pim kinase inhibitors that potently inhibit all three Pim kinases with sub nanomolar to low single-digit nanomolar Ki values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones including PDB IDs 3JYA, 3JYOand 3JXW were determined and used to guide SAR studies. Tao et al. designed and synthesized a number of 69 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-one compounds and evaluated their biological activities against Human Proto oncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases. Many of these compounds exhibited potent antiproliferative activity in human K562 and MV4-11 cancer cells with sub-micromolar EC₅₀ values (Tao et al., 2009).

To date, the development of inhibitors having a specific affinity towards Pim-1, Pim-2 and Pim-3 kinases is scarce. Therefore, it was our aim to model properties of Pim-1 and Pim-2 inhibitors responsible for the anticancer activities. In this connection, the toxicity of Pim kinase inhibitors should also be considered. It was reported that novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating that they are effective and with a favorable toxicity profile (Mondello et al., 2014). The cardiotoxicity due to inhibition of the cardiac potassium channel human ether-à-go-go-related gene was observed with Pim inhibitor SGI-1776 (Foulks et al., 2014).