Abstract 3579: Discovery and anticancer preclinical evaluation of novel piperazinylpyrimidine derivatives designed to target the human kinome
Authors: Shallal Hassan , Russu Wade 
Published: February 2011

The human kinome represents over 518 discovered protein kinases, some of which have been positively or negatively linked to the pathophysiology of several human ailments like cancer, rheumatoid arthritis, diabetes, and neurodegenerative diseases. Targeting those clinically validated kinases has proven useful in managing many of those illnesses. A novel class of kinase inhibitors was structurally designed based on the attachment of piperazinylpyrimidine core with kinase privileged fragments. The study aimed to investigate the in vitro cellular cytotoxic activity of the novel derivatives along with their kinase binding profile. Twenty final novel compounds were successfully synthesized and structurally confirmed using analytical and spectroscopic techniques. In a primary screening against A549 and MCF-7 cell lines, 9 derivatives were almost inactive while the remaining derivatives showed an interesting range of cytotoxic activity against the two cell lines. 10 compounds were accepted for one-dose screening against the NCI-60 panel. 8 compounds were chosen for determining their dose response against the NCI-60. The antiproliferative activity ranged from very weakly active (II-25, mean GI50 &gt; 100 μM) to strongly cytotoxic (II-20, mean GI50 = 1.05 μM). I-11, I-12, and II-18 showed an interesting pattern of very potent and selective cytotoxic activity towards a few cell lines of different histological origin. For example, II-18 showed a GI50 of 90 nM against NCI-H23 (NSCLC), 68 nM against RPMI-8226 (leukemia), 61 nM against SK-MEL-5 (melanoma) and 30 nM against MDA-MB-468 (breast cancer). Additionally, there was found a very wide window between the mean GI50 and the mean LC50 of these three compounds. For instance, the mean GI50 of I-12 is 5.25 μM while its mean LC50 is &gt; 100 μM. Furthermore, I-11, I-12, and II-18 conform to Lipinski's rule of five of drug-likeliness. Accordingly, I-11, I-12, and II-18 are scheduled, at the time of submitting this abstract, for retesting against the NCI-60 in order to confirm their potential to reproduce this selective cytotoxic profile on the cellular level. Concerning the kinase binding profile of 10 μM concentration of I-12, II-16 and II-20, the results of the KINOMEscan™ revealed that I-12 binds mostly to PDGFR tyrosine kinase subfamily (KIT, KIT (D816V), FLT3, PDGFRA. PDGFRB, and CSF1R). I-12 also strongly targets CDK11 and modestly can inhibit DDR1 and CSNK1D kinases. On the other hand, II-16 and II-20 (structurally different than I-12) can bind to DDR1, CSNK1D, and CSNK1G2 kinases. From the above study, it can be inferred that piperazinylpyrimidine core represents a promising core for the design of novel derivatives which can exhibit a potential of potent as well as selective cytotoxicity and kinase binding.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3579.