Abstract
Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50) values of 4.5, 3.0, and 3.9 nM, respectively, which were comparable to idelalisib (IC50 = 2.7 nM). The further PI3K isoforms selectivity evaluation showed that compounds 12d, 14b and 14c have excellent PI3Kδ selectivity over PI3Kα, PI3Kβ, and PI3Kγ. Moreover, compounds 12d, 14b and 14c also displayed different anti-proliferative profiles against a panel of four human B cell lines including Ramos, Raji, RPMI-8226, and SU-DHL-6. The molecular docking simulation indicated several key hydrogen bonding interactions were formed. This study suggests the introduction of pyrrolidineoxy or piperidineamino groups into the 4-position of quinazoline leads to new potent and selective PI3Kδ inhibitors.
Highlights
Phosphoinositide 3-kinases (PI3Ks) play a pivotal role in multiple cellular functions including cell growth, development, migration, angiogenesis, and survival[1]
Phosphoinositide 3-kinase Delta (PI3Kd) is found responsible for the B-cell receptor (BCR) signaling downstream transduction and constitutive studies show activation of BCR signaling pathway is a hallmark of B-cell malignancies such as chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), and indolent nonHodgkin’s lymphoma[4]
Small molecules selective PI3Kd inhibitor idelalisib (Compound 1) has been recently approved by Food and Drug Administration (FDA) for treatment of CLL, FL, and SLL, which solidify the therapeutic concept of PI3Kd inhibitor (Figure 1)[6,7]
Summary
Phosphoinositide 3-kinases (PI3Ks) play a pivotal role in multiple cellular functions including cell growth, development, migration, angiogenesis, and survival[1]. Further structural investigation by replacing the 4-aniline with a 4-pyrrolidineamino moiety led to a series of potent and selective PI3Kd inhibitors, such as Compound 9 (PI3Kd: IC50 1⁄4 2.7 nM), showing equivalence to idelalisib in our examination (Figure 1)[17]. Encouraged by these fantastic findings, we decided to develop a new series of quinazoline based PI3Kd inhibitors by introducing functionalised pyrrolidineoxy or piperidineamino group at the 4-position of quinazoline instead of the pyrrolidineamino moiety. Piperidineamino substituted quinazolines as potent and selective PI3Kd inhibitors (Figure 2)
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