Structural, Biochemical, and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-Kinase δ

Somoza, John R.; Koditek, David; Villaseñor, Armando G.; Novikov, Nikolai; Wong, Melanie; Liclican, Albert; Xing, Weimei; Lagpacan, Leanna; Wang, Ruth; Schultz, Brian E.; Papalia, Giuseppe A.; Samuel, Dharmaraj; Lad, Latesh; McGrath, Mary E.

doi:10.1074/jbc.m114.634683

Cited by 148 publications

(142 citation statements)

References 34 publications

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“…In crystal structure evaluation of PI3Kd in complex with idelalisib, the electron density of idelalisib showed that there was no The reversibility of idelalisib binding was also demonstrated using surface plasmon resonance studies, with saturable, dose-response interaction with p110d, a very fast on-rate and a moderate off-rate. The response signal in these studies returned to the baseline level during the dissociation phase, indicating complete dissociation, in contrast with the control agent (wortmannin), which was irreversibly bound to p110d [18].…”

Section: Introductionmentioning

confidence: 51%

Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib

et al. 2015

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Idelalisib is a potent and selective phosphatidylinositol 3-kinase-δ inhibitor, which is a first-in-class agent to be approved for the treatment of relapsed chronic lymphocytic leukaemia, follicular B cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. In dose-ranging studies, idelalisib exposure increased in a less than dose-proportional manner, likely because of solubility-limited absorption. The approved starting dose of 150 mg twice daily was supported by extensive exposure-response evaluations, with dose reduction to 100 mg twice daily being allowed for specific toxicities. Idelalisib may be administered without regard to food on the basis of the absence of clinically relevant food effects, and was accordingly dosed in primary efficacy/safety studies. Idelalisib is metabolized primarily via aldehyde oxidase (AO) and, to a lesser extent, via cytochrome P450 (CYP) 3A. Coadministration with the strong CYP3A inhibitor ketoconazole 400 mg once daily resulted in a ~79 % increase in the idelalisib area under the plasma concentration-time curve (AUC). Administration with the potent inducer rifampin resulted in a 75 % decrease in idelalisib exposure (AUC) and, as such, coadministration with strong inducers should be avoided. GS-563117 is an inactive primary circulating metabolite of idelalisib formed mainly via AO. Unlike idelalisib, GS-563117 is a mechanism-based inhibitor of CYP3A. Accordingly, idelalisib 150 mg twice-daily dosing increases the midazolam AUC 5.4-fold. Clinically, idelalisib is not an inhibitor of the transporters P-glycoprotein, breast cancer resistance protein, organic anion-transporting polypeptide (OATP) 1B1 or OAPT1B3. In a population pharmacokinetic model, no meaningful impact on idelalisib pharmacokinetics was noted for any of the covariates tested. Idelalisib exposure was ~60 % higher with moderate/severe hepatic impairment; no relevant changes were observed with severe renal impairment. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies and mechanistic and special population studies, which has allowed a thorough understanding of idelalisib clinical pharmacokinetics and their impact on clinical safety and efficacy.

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Section: Introductionmentioning

confidence: 51%

Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib

et al. 2015

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“…The crystal complex of PI3Kd with idelalisib revealed a type II binding that is similar to that of another selective PI3Kd inhibitor, PIK39 [100]. Idelalisib adopts a propeller-shaped conformation with the DFG motif posing in an 'out' conformation [101]. The 5-fluoroquinazolinone moiety squeezes into an induced hydrophobic specificity pocket.…”

Section: Approved Lipid Kinase Inhibitorsmentioning

confidence: 96%

“…The ethyl group binds in a hydrophobic pocket and the phenyl group extends into a hydrophobic region that is close to the solvent front. The hinge hydrogen bond, which is a highly conserved feature for PI3K inhibition [102], is formed between Val828 and the purine moiety that occupies the adenine pocket [101] ( Figure 14B,C). Besides being approved for CLL, idelalisib has also been granted accelerated approval for relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma [103,104].…”

Section: Approved Lipid Kinase Inhibitorsmentioning

confidence: 97%

FDA-approved small-molecule kinase inhibitors

Nielsen

Clausen

2015

Trends in Pharmacological Sciences

865

739

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Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure-activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.

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“…Furthermore, the quinazolinone derivatives as novel PI3Kd selective inhibitors have the same structure skeleton with idelalisib, so the co-crystal structure of PI3Kd protein with idelalisib was downloaded from the Protein Data Bank (PDB ID: 4XE0) for the molecular docking study. 29 …”

Section: Data Setsmentioning

confidence: 99%

Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors

2017

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The forced expression of phosphoinositide 3-kinase d (PI3Kd) in B cells was found to be oncogenic, rendering PI3Kd an attractive drug target for chronic lymphocytic leukaemia. This study aimed to systemically explore the interaction mechanism of novel quinazolinone scaffold-based derivatives as PI3Kd inhibitors using 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics (MD) simulations. The 3D-QSAR models CoMFA, CoMSIA and Topomer CoMFA were established to discover critical structural factors affecting PI3Kd inhibitory activity. The models showed suitable reliabilities (q 2 0.741, 0.712 and 0.711) and predictive abilities (r pred 2 0.851, 0.738 and 0.828, respectively).Contour maps indicated that the bioactivity of PI3Kd inhibitor was affected most by electrostatic and hydrophobic fields. The Surflex-Dock and pharmacophore model result showed that enhancing the Hbond interaction of the key substituents around the 2-and 4-positions of pyrimidine with Glu826, Val828 and Asp911, as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831, Asp832 and Asn836, significantly affected the improvement in the activity and stability of the inhibitor. Based on these results, 10 novel PI3Kd inhibitors with higher predicted activity and binding affinity were designed by introducing the heterocycles pyrrolopyridine or purine. 10 ns MD simulations further study the stable docking conformation of designed compounds, which showed strong hydrogen bond interactions with key residues Ser831 and Asp832 in a propeller-like fashion.These results provided strong guidance for the discovery and optimization of novel potent PI3Kd selective inhibitors.

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Structural, Biochemical, and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-Kinase δ

Cited by 148 publications

References 34 publications

Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib

Clinical Pharmacokinetic and Pharmacodynamic Profile of Idelalisib

FDA-approved small-molecule kinase inhibitors

Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors

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