Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma

Wang, Wanhe; Naganna, Nimishetti; Sintim, Herman O.

doi:10.1016/j.bioorg.2019.103052

Cited by 15 publications

(16 citation statements)

References 27 publications

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“…HSN748 and other analogs (Figure ) were synthesized in two linear steps from 5-ethynylnicotinic acid (Figure ). − By introducing a nitrogen into the benzamide ring (to make a nicotinamide), the calculated log P changed from 4.29 (ponatinib) to 3.62 (HSL420). Removing the methyl group on HSL420 reduced the c log P even further to 3.23 (HSN748) .…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

et al. 2020

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Ponatinib is a multikinase inhibitor that is used to treat chronic myeloid leukemia patients harboring mutated ABL1(T315I) kinase. Due to the potent inhibition of FLT3, RET, and fibroblast growth factor receptors (FGFRs), it is also being evaluated against acute myeloid leukemia (AML), biliary, and lung cancers. The multikinase inhibition profile of ponatinib may also account for its toxicity, thus analogs with improved kinase selectivity or different kinase inhibition profiles could be better tolerated. The introduction of nitrogen into drug compounds can enhance efficacy and drug properties (a concept called “necessary nitrogen”). Here, we introduce additional nitrogen into the benzamide moiety of ponatinib to arrive at nicotinamide analogs. A nicotinamide analogue of ponatinib, HSN748, retains activity against FLT3, ABL1, RET, and PDGFRα/β but loses activity against c-Src and P38α. MNK1 and 2 are key kinases that phosphorylate eIF4E to regulate the protein translation complex. MNK also modulates mTORC1 signaling and contributes to rapamycin resistance. Inhibitors of MNK1 and 2 are being evaluated for anticancer therapy. Ponatinib is not a potent inhibitor of MNK1 or 2, but the nicotinamide analogs are potent inhibitors of MNKs. This illustrates a powerful demonstration of the necessary nitrogen concept to alter both the potency and selectivity of drugs.

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Section: Resultsmentioning

confidence: 99%

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

et al. 2020

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“…The study showed that the median PFS was 4.5 months, the median OS was 11.6 months ( Table 1 ). The most common grade 3 AEs were hypertension (17%), a prolonged QTc interval (11%), and transaminitis (6%) ( 39 ).…”

Section: Nonselective Multitargeted Tkismentioning

confidence: 99%

Research Progress on RET Fusion in Non-Small-Cell Lung Cancer

Zhao

Mei

et al. 2022

Front. Oncol.

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Great progress has been made in the treatment of driver gene-positive Non- Small Cell Lung Cancer (NSCLC) in recent years. RET fusion was seen in 0.7% to 2% of NSCLC and was associated with younger age and never-smoker status. The pralsetinib and selpercatinib for RET fusion NSCLC was recommended by the 2021 NSCLC treatment guidelines. This review outlines the research progress in the treatment of RET fusion NSCLC, identifies current challenges and describes proposals for improving the outlook for these patients.

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“…Nearly one-third of initially responding patients have shown relapse over time by developing secondary mutations during treatment . Sintim and co-workers discovered HSN608 ( 5 ) (Scheme ) as a lead compound with high potency toward inhibition of all FLT-3 forms. ,, This lead also displays inhibition activity toward RET and its mutant forms better than the reported RET inhibitors . In order to support the drug development effort to enable in vivo experiments and toxicology studies for this lead compound, identification of a synthetic route that can be rapidly upscaled is essential.…”

Section: Introductionmentioning

confidence: 99%

“…6a,7,9 This lead also displays inhibition activity toward RET and its mutant forms better than the reported RET inhibitors. 7 In order to support the drug development effort to enable in vivo experiments and toxicology studies for this lead compound, identification of a synthetic route that can be rapidly upscaled is essential.…”

Section: ■ Introductionmentioning

confidence: 99%

Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

Biyani

et al. 2020

Org. Process Res. Dev.

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Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.

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Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma

Cited by 15 publications

References 27 publications

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds

Research Progress on RET Fusion in Non-Small-Cell Lung Cancer

Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

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