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1.
Proc Natl Acad Sci U S A ; 121(6): e2317756121, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38300868

RESUMO

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Hiperfosfatemia , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Ductos Biliares Intra-Hepáticos/metabolismo , Diarreia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química
2.
Angew Chem Int Ed Engl ; 55(46): 14218-14238, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27723189

RESUMO

Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.


Assuntos
Preparações Farmacêuticas/química , Elementos de Transição/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Carbono/química , Catálise , Técnicas Eletroquímicas , Hidrogênio/química , Técnicas Analíticas Microfluídicas , Oxirredução , Preparações Farmacêuticas/metabolismo
3.
J Am Chem Soc ; 135(33): 12346-52, 2013 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-23875728

RESUMO

The isolation, quantitation, and characterization of drug metabolites in biological fluids remain challenging. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Herein, we compared biotransformations to classical and new chemical C-H oxidation methods using oxcarbazepine, naproxen, and an early compound hit (phthalazine 1). These studies illustrated the low preparative efficacy of biotransformations and the inability of chemical methods to oxidize complex pharmaceuticals. We also disclose an aerobic catalytic protocole (CuI/air) to oxidize tertiary amines and benzylic CH's in drugs. The reaction tolerates a broad range of functionalities and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.


Assuntos
Aminas/química , Carbono/química , Cobre/química , Hidrogênio/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Biotransformação , Catálise , Oxirredução , Especificidade por Substrato
4.
Cancer Discov ; 13(9): 2012-2031, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37270847

RESUMO

Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Mutação , Colangiocarcinoma/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
5.
J Org Chem ; 75(15): 4911-20, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20608749

RESUMO

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.


Assuntos
Imidazóis/química , Alquilação
6.
J Med Chem ; 60(5): 2155-2161, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28186750

RESUMO

While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.


Assuntos
Inibidores Enzimáticos/farmacologia , Zíper de Leucina , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Cristalografia por Raios X , Inibidores Enzimáticos/química
7.
Structure ; 25(3): 506-513, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28132785

RESUMO

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.


Assuntos
Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/genética , Neoplasias/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação Alostérica , Sítio Alostérico , Cristalografia por Raios X , Glutaratos/metabolismo , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética
8.
ACS Med Chem Lett ; 8(2): 151-156, 2017 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-28197303

RESUMO

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

9.
Org Lett ; 8(10): 1979-82, 2006 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-16671761

RESUMO

[reaction: see text] The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties is reported. These complexes catalyze the efficient C-H arylation of SEM-protected azole heteroarenes and thus provide a good method for preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is operationally simple; the complexes are insensitive to moisture.

10.
J Med Chem ; 59(10): 4711-23, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27187609

RESUMO

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/normas , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade
11.
ACS Med Chem Lett ; 4(2): 186-90, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24900652

RESUMO

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

12.
J Med Chem ; 56(16): 6495-511, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23844574

RESUMO

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.


Assuntos
Acetamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirimidinonas/farmacologia , Tanquirases/antagonistas & inibidores , Acetamidas/administração & dosagem , Acetamidas/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Inibidores Enzimáticos/administração & dosagem , Camundongos , Modelos Moleculares , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Relação Estrutura-Atividade
13.
Chem Commun (Camb) ; 48(53): 6735-7, 2012 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-22643736

RESUMO

The first TiCl(4)-mediated condensation of secondary amides with aldehydes and ketones has been achieved. The reaction proceeds at room temperature and is complete within 5 h in most cases. The optimized procedure used 5 equiv of an amine base hinting that the in situ activation of both the amide and the Lewis acid is required. The reaction affords polysubstituted (E)-enamides.


Assuntos
Aldeídos/química , Amidas/química , Cetonas/química , Estrutura Molecular , Titânio/química
14.
ACS Med Chem Lett ; 3(7): 579-83, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900514

RESUMO

The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π-π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.

15.
Org Lett ; 12(7): 1532-5, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20196553

RESUMO

We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides. The electronic factors that influence the course of the reaction have also been investigated.


Assuntos
Cobre/química , Iodetos/química , Sulfonamidas/química , Sulfonamidas/síntese química , Estrutura Molecular , Estereoisomerismo
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