Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines

Zhao, Dan; Huang, Shanshan; Qu, Menghua; Wang, Changyuan; Liu, Zhihao; Li, Zhen; Peng, Jinyong; Liu, Kexin; Li, Yanxia; Ma, Xiaodong; Shu, Xiaohong

doi:10.1016/j.ejmech.2016.11.047

Cited by 28 publications

(9 citation statements)

References 29 publications

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“…3 BTK is an integral component of the B-cell receptor signaling complex with expression limited primarily to B lymphocytes, mast cells, monocytes, and osteoclasts 4,5 and plays an important role in the B-cell signaling pathway linking cell surface B-cell receptor stimulation to downstream intracellular responses. [6][7][8] The highly restricted expression pattern of BTK together with the prominent role of BTK in the B-cell receptor signaling pathway makes it an attractive drug target for the treatment of B-cell malignancies. It has been reported that numerous B-cell-derived malignancies, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, mantle-cell lymphoma, Waldenstrom macroglobulinemia, and multiple myeloma, are dependent on disregulation of BTK kinase activity.…”

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confidence: 99%

“…It has been reported that numerous B-cell-derived malignancies, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, mantle-cell lymphoma, Waldenstrom macroglobulinemia, and multiple myeloma, are dependent on disregulation of BTK kinase activity. [8][9][10] Ibrutinib, a novel first-in-class BTK inhibitor, has been approved by various regulatory agencies for the treatment of mantle-cell lymphoma, CLL, and Waldenstrom macroglobulinemia. 11 More selective and potent BTK inhibitors are currently being investigated clinically.…”

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confidence: 99%

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Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Li¹,

Ramírez‐Valle²,

Xue³

et al. 2017

The Journal of Clinical Pharma

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CC‐292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B‐cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC‐292 and assess the influence of demographics and disease‐related covariates on CC‐292 exposure and to assess the exposure‐response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2‐compartment base model conducted in NONMEM. Categorical exposure‐response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC‐292 pharmacokinetic disposition is similar between healthy subjects and patients. CC‐292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC‐292, clearance from blood occurs faster than distribution into deep tissues and organs. CC‐292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure‐response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice‐daily dose regimen showed higher overall response rate as compared to once‐daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases.

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confidence: 99%

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confidence: 99%

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Li¹,

Ramírez‐Valle²,

Xue³

et al. 2017

The Journal of Clinical Pharma

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“…Thus, inhibition of BTK activity can provide a useful treatment for allergic disorders, autoimmune, and/or inflammatory diseases such as, rheumatoid arthritis, idiopathic thrombocytopenic purpura, asthma, and other related disorders . Due to our great interest in the identification of potent BTK inhibitors for the treatment of B‐cell lymphoma, we accidentally obtained a class of pyrimidine derivatives, which exhibited strong activity against BTK, JAK3, and EGFR kinases at a drug concentration of 10 nM or less. Considering the important role of these kinase in the development of IPF, we believe that these multi‐PTK inhibitors are effective in treatment of the IPF disease.…”

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confidence: 99%

Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Sun¹,

Liu

et al. 2019

ChemMedChem

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A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small‐molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N‐(3‐((5‐chloro‐2‐(4‐((1‐morpholino)acetylamino)phenylamino)‐4‐pyrimidinyl)amino)phenyl)acrylamide (6 a) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi‐PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.

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“…They include Ibrutinib, which was approved in 2013 for treating Chronic Lymphocytic Leukemia (CLL, the commonly found leukimia in Western countries), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM) [3,5,6]. Other BTK inhibitors such as ONO-4059, CC-292, and acalabrutinib (Acerta Pharma BV, the Netherlands) are still in clinical tests for B-cell malignancies and autoimmune disorders treatments [7][8][9][10]. It is well known that the finding of new molecules with improved drug efficacy require a large amount of resources of both time and cost.…”

Section: Introductionmentioning

confidence: 99%

Identification of potential inhibitors for Bruton’s Tyrosine Kinase (BTK) based on pharmacophore-based virtual screening

2020

Biointerface Res Appl Chem

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Bruton’s tyrosine kinase (BTK) is well known for its role in the development, differentiation and proliferation of B-lineage cells. The dysregulation of BTK is closely related with the immunological disorders and BTK targeting is commonly studied in the treatment of immunological disorders. Here pharmacophore model was developed, and screening against ZINC database retrieved 1337 hit molecules of potential BTK inhibitors. Molecular docking was performed for all molecules and analysis on the top docked molecules revealed that the ligands interacted well in the binding pocket of BTK. A 100-ns molecular dynamics simulation confirmed the docked pose of ligand, while the calculation of binding free energy indicated that the hit molecule has comparable affinity with native ligand of BTK (2V3).

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Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines

Cited by 28 publications

References 29 publications

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia

Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Identification of potential inhibitors for Bruton’s Tyrosine Kinase (BTK) based on pharmacophore-based virtual screening

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