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Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib.

ABSTRACT: Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.

SUBMITTER: Radaram B

PROVIDER: S-EPMC7193943 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib.

Radaram Bhasker B Pisaneschi Federica F Rao Yi Y Yang Ping P Piwnica-Worms David D Alauddin Mian M MM

European journal of medicinal chemistry 20190809

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no ...[more]

PMID: 31425908

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Project description:Background:This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods:ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600?mg twice daily or chemotherapy (pemetrexed 500?mg/m2 or docetaxel 75?mg/m2, both every 3?weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). Results:Altogether, 107 patients were randomized (alectinib, n?=?72; chemotherapy, n?=?35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6?months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4?months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P?<?0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1?months (95% CI: 6.3-10.8) with alectinib and 1.6?months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n?=?24; chemotherapy, n?=?16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P?<?0.001). Grade ?3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1?weeks versus 6.0?weeks). Conclusion:Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registration:ClinicalTrials.gov NCT02604342; Roche study MO29750.

Project description:BackgroundThe phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.Patients and methodsOverall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.ResultsIn total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.ConclusionAlectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.Clinical trial registrationClinicalTrials.gov NCT02075840.

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Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib.

Publications

Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib.

Similar Datasets

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