Research paperDiscovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity
Introduction
Phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases which can be divided into three main classes (Class I, II and III) depending on their sequence homology [[1], [2], [3]]. In mammals, class IA PI3Ks includes PI3Kα, PI3Kβ and PI3Kδ, while class IB includes PI3Kγ [1,[4], [5], [6]]. Among four types of PI3Ks, PI3Kδ is expressed dominantly in hematopoietic cells and plays a vital role in B-cell malignancies via PI3K/Akt signaling pathway [[7], [8], [9]]. Therefore, it has been a promising approach for curing B-cell malignancies by specifically targeting PI3Kδ to avoid potential side effects associated with the ubiquitously expressed PI3Kα, β and γ isoforms. There are a number of PI3K inhibitors have been approved by FDA for the treatment of B-cell malignancies. Idelalisib (Fig. 1), the first-in-class PI3Kδ-selective inhibitor, is approved by FDA for treating chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) [10,11]. Copanlisib is a pan-PI3K inhibitor with preferential activity against PI3Kα and PI3Kδ, which was approved for relapsed FL. Duvelisib was approved for treating hematopoietic malignancies as a PI3Kδ/γ dual inhibitor. Several other candidates (Fig. 1), such as Acalisib [12], Umbralisib [13], Seletalisib [14], Dactolisib [15] and Leniolisib [9,16], are currently in clinical trials as remedies for the treatment of B or T cell-related malignancies. Given potential applications of PI3Kδ inhibitors in B-cell malignancies, there has been significant interests to identify highly selective PI3Kδ inhibitors through optimization of clinically used inhibitors.
We started our efforts by deconstructing the imidazoquinoline scaffold of Dactolisib (BEZ235) to quinazoline skeleton as the hinge region binding moiety (Fig. 2). In addition, considering the affinity pocket conserved in all PI3K isoforms, we supposed that the nonconserved pocket at the entrance of the PI3K ATP binding pocket might be the optional approach to improve the selectivity of ligand [17]. Based on this speculation, we are trying to change the electronic effect of the terminal segment in order to form an extra interaction with the nonconserved region. As a result, the electron deficient acrylamide fragment, which has never been explored on this target, was introduced as the terminus of quinazoline core. We envisioned that this design might be a feasible approach to obtaining the highly selective PI3Kδ inhibitors. In brief, in this paper, the potential of these compounds as selective PI3Kδ inhibitors is detailed by describing their synthesis, biological evaluation and SARs, resulting in compound 15c as a potent PI3Kδ inhibitor with higher PI3K isoform-selectivity than BEZ235.
Section snippets
Chemistry
As summarized in Scheme 1, condensation of commercially available 2-amino-5-bromobenzoic acid 1 and formamidine acetate gave 6-bromo-4-hydroxyquinazoline 2 in high yield, which was subsequently converted to 6-bromo-4-chloro quinazoline 3 in the presence of thionyl chloride. In another route, acylation of 3-nitroaniline 4 with acryloyl afforded compound 5 of which the mitro group was reduced by iron to generate intermediate 6. Coupling reaction between 3 and 6 produced key intermediate 7 which
Conclusion
In present work, we have identified a series of PI3Kδ inhibitors based on acrylamide fragments resulting in the discovery of lead compound 15c, which exhibited potent target activity (IC50 = 27.5 nM) and excellent selectivity over other PI3K isoforms. Additionally, the prominent anti-proliferation activities and potent suppression of Akt phosphorylation in Raji cells of 15c make it a promising compound for the treatment of B cell malignancies. However, the poor metabolic stability prompt us to
Chemistry
Starting material and solvents were purchased from commercial sources. Reactions were monitored by thin-layer chromatography (TLC) using precoated silica gel plates (silica gel GF/UV 254), and spots were visualized under UV light (254 nm). Melting points (uncorrected) were determined on a Mel-TEMP II melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded with a Bruker Avance 300 MHz spectrometer at 300 K, using TMS as an internal standard. MS spectra or
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
We are grateful to the Program of Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University. This work was supported by grants from Natural Science Foundation of China (NSFC, 81874286); “Double-First-Class” University Project CPU 2018PZQ02 and CPU 2018GY07. We are grateful to the College students’ innovation and entrepreneurship training program (201910316002G) for the financial support of this research.
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