Optimization of Ligand and Lipophilic Efficiency To Identify an in Vivo Active Furano-Pyrimidine Aurora Kinase Inhibitor

Abstract

Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.

Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives

“…Copper(I)-catalysed click reaction of 5-iodo-N-1-propargylpyrimidine (2) with corresponding azides followed by Sonogashira cross-coupling reaction with terminal alkynes gave novel 1,4-disubstituted 1,2,3-triazole tethered 5-alkynylpyrimidine (14-19) and 6-substituted furo [2,3-d]pyrimidines (20)(21)(22). In vitro antiproliferative activity of novel compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that 3,5-difluorophenyl and p-(trifluoromethyl)phenyl substituents in pyrimidine (19) and furo [2,3- …”

“…[10][11][12][13][14][15] Thus, furo [2,3-d]pyrimidine attract considerable attention due to their great practical significance through exerting pharmacological potential as antiviral, antimicrobial, and antitumor agents, and is one of the most recently explored scaffolds to have potential anticancer activity through inhibition of various protein kinases. [16][17][18][19] Besides, it was found that some 1,2,3-triazole tethered pyrimidine nucleosides, [20] 1,2,3-triazole pyrimidine nucleoside conjugates with the 1,2,3-triazole as a substituent at the pyrimidine ring, [21] the sugar moiety [22] or sugar mimic [23] were endowed with a pronounced cytostatic activity. [24] In continuation of our efforts towards the hybridisation of pyrimidine and 1,2,3-triazole scaffolds into a single chemical entity, [25] we report here the synthesis and biological investigations of C-5 alkynylated pyrimidines and C-6-alkylated furo [2,3-d]pyrimidines containing N-1-substituted 1,2,3-triazole ring.…”

Identification of ligand efficient, fragment-like hits from an HTS library: structure-based virtual screening and docking investigations of 2H- and 3H-pyrazolo tautomers for Aurora kinase A selectivity

“…Aurora kinase A/B [17] and EGFR kinase [23] inhibition assays for the compounds were carried as previously described.…”

“…VX-680 is a non- selective Aurora inhibitor with Aurora A IC 50 = 20 nM and Aurora B IC 50 = 30 nM [17]. Docking of both the major tautomer-1 (taut-1, 97 %) and minor tautomer-2 (taut-2, 3 %) was carried out and the results summarized in Table 3.…”

“…Lead 2 showed anti-proliferative activity in a colon cancer cell line (HCT-116) in vitro, but failed to suppress HCT-116 proliferation in vivo (xenograft mouse model). Further modifications of lead 2 resulted in compounds with in vivo efficacy, but none of these compounds were orally bioavailable [16,17].…”