4-Aminoindazolyl-dihydrofuro[3,4- d ]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase

Hanan, Emily J.; Baumgardner, Matt; Bryan, Marian C.; Chen, Yuan; Eigenbrot, Charles; Fan, Peter W.; Gu, Xiao-Hui; La, Hank; Malek, Shiva; Purkey, Hans E.; Schaefer, Gabriele; Schmidt, Stephen; Sideris, Steve; Yen, Ivana; Yu, Christine; Heffron, Timothy P.

doi:10.1016/j.bmcl.2015.11.078

Cited by 43 publications

(34 citation statements)

References 28 publications

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“…According to metabolite identification of [ 14 C]-anlotinib hydrochloride, the main metabolic pathways of anlotinib hydrochloride include: (1) amino oxidation (amino to hydroxyl) to form M28; (2) mono-oxidation to form M1, and further to oxidative metabolite (M2) and sulfuric acid conjugate (M9); (3) carboxylation to form M30. Additionally, the secondary metabolic pathways of anlotinib hydrochloride in the patients including: (1) mono-oxidation to form M23 and/or M46/M66 and further convert to glucuronic acid-binding product (M17); (2) O-dealkylation to form M18 [15].…”

Section: Discussionmentioning

confidence: 99%

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Liu

Wang

et al. 2020

Cancer Chemother Pharmacol

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Purpose Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. Methods Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [ 14 C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [ 14 C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [ 14 C]-anlotinib were collected. The absorption, metabolism, and excretion of [ 14 C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. Results In plasma, the average time to peak concentration (T max) of total radioactivity was 4.42 h and the average peak concentration (C max) of total radioactivity was 18.80 ng Eq./g. The average values of AUC 0-last , AUC 0-∞ , and MRT 0-t were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. Conclusions Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected.

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Section: Discussionmentioning

confidence: 99%

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Liu

Wang

et al. 2020

Cancer Chemother Pharmacol

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“…[21,22] Hanan et al identified 4-aminoindazolyldihydrofuro [3,4-d]pyrimidine (8)a sapotent TMLR (T790M/L858R) inhibitor,w ith a K i value of 2nm and moderate activity in ac ellbased assay (H1975 pEGFR IC 50 = 0.60 mm)b yh igh-throughput screening of their internal compound library ( Figure 3). [23] How-ever,this compound exhibited high clearance and low oral bioavailability (F = 13 %). Given that the primary metabolites were produced by oxidationo ft he indazole ring, the authors attempted to optimize this lead compound through addition of substituents to the indazole motif, or replacement of indazole and pyrazole moieties by other heterocycles.…”

Section: Inhibition Of Egfrmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.

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“…Also, they were orally bioavailable and permeable. Most especially the five lead compounds (7,19,22, 27 and 34). The Bioavailability Radar of the five lead compounds (7,19,22, 27 and 34) under investigation was shown to further confirm their drug-likeness properties (Fig.…”

Section: Molecular Docking Simulation Of Investigated Compoundsmentioning

confidence: 99%

“…Report on NSCLCs on the population of patients in Caucasia rise to about 10-15% and 30-40% in Asia [4,5] The discovery of inhibitors for EGFR enzyme is one of the challenges encountered by researchers in the field of medicinal chemistry [6]. Therefore, the development of NSCLC agents/EGFR inhibitors to treat non-small cell lung cancers is an important medical need [7]. Numerous NSCLC agents were discovered starting from the so-called first-generation, followed by the second, third and up to forth generations.…”

Section: Introductionmentioning

confidence: 99%

Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

2020

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Purpose Cancer was recognised to be daunting illness and second cause of death worldwide. The death estimate caused by cancer as of 2012 was about 17% of the total deaths (which is about 8.5 million) and in 2030 will be about 13.1 million deaths. Lung cancer is one of the leading cancer problems in the globe. It was reported to cause a lot of death every year. In all types of cancer, non-small cell lung cell (NSCLC) is one of the various causes of cancer-related mortality. Therefore there is need to design more potent NSCLC therapeutic agents. The purpose of this work is to identify lead compounds among the investigated ant-cancer agents with prominent activity against NSCLC and also design new NSCLC therapeutic agents by carrying out structural modification on the best lead compound using Structure-based approach. Method The method employed in this research is structure-based drug design approach on some anti-cancer agents. It involves molecular docking which study how these anti-cancer agents interact in with active site of their target protein (EGFR receptor PDB code: 4ZAU) and identify which among the investigated molecules have the lowest docking score/ highest binding affinity toward the target and then predict their pharmacokinetic profile. The best among them will be used as template for designing new NSCLC therapeutic agents with higher affinity toward EGFR receptor. Result The investigation of the binding mode of some NSCLC therapeutic agents against EGFR receptor (PDB: 4ZAU) was achieved through docking in this research. Five compounds exhibited the best docking scores among the docked ligands were compound 7, 19, 22, 27 and 34. Compound 19 and 27 under investigation were found to have the lowest docking score of-9.7 kcal/mol among the compounds under investigation. Compound 19 was seen to interact in the binding site of EGFR receptor through electrostatic interaction with LYS745 amino acid residue of the EGFR receptor, hydrophobic interaction with LYS745, VAL726, ALA743, LEU844 and LEU718 amino acid residues and hydrogen bond interaction with GLU762 (2.69145 Å), ASP855 (2.78155 Å) and LYS745 (3.05463 Å) amino acid residues in the binding site of EGFR receptor which might be responsible for the lowest energy (highest docking score) of the ligand. The ADME/Pharmacokinetics and druglikeness of these lead compounds and compound 27 were predicted and observed to be orally bioavailable because none of them broke more than the allowable limit by Lipinski's RO5 filters. Compound 27 was retained and used as a template for the designing process. Thirteen (13) new NSCLC therapeutic agents were designed were designed by carrying out structural modification on methyl group attached to '1, 2, 4 triazolo pteridinone' moiety and two methyl groups attached to 'piperidin-1-yl' of the template. Conclusion The molecular docking simulation, ADME/Pharmacokinetics and drug-likeness employed on some NSCLC therapeutic agents discovered five compounds (7, 19, 22, 27 and 34) with the lowest docking scores among other compounds ...

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4-Aminoindazolyl-dihydrofuro[3,4- d ]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase

Cited by 43 publications

References 28 publications

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Recent Advances in the Development of Indazole‐based Anticancer Agents

Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

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