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2.
Bioorg Med Chem Lett ; 26(8): 2065-7, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26951750

RESUMO

We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9 nM) was identified following this approach.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 26(8): 2057-64, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26951753

RESUMO

Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Nus , Estrutura Molecular , Células NIH 3T3 , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Angew Chem Int Ed Engl ; 54(48): 14575-9, 2015 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-26457482

RESUMO

Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.


Assuntos
Osso e Ossos/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Administração Oral , Disponibilidade Biológica , Osso e Ossos/enzimologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Geraniltranstransferase/antagonistas & inibidores , Humanos
5.
Bioorg Med Chem Lett ; 22(5): 1860-3, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22335894

RESUMO

Aromatase inhibition is the new standard of care for estrogen receptor positive breast cancer and has also potential for treatment of other diseases such as endometriosis. Simple and readily available 3-pyridyl arylethers and 1-aryl pyrrolo[2,3-c]pyridines recapitulating the key pharmacophore elements of Letrozole (1) are described and their structure-activity relationships are discussed. Potent and ligand efficient leads such as compound 23 (IC(50)=59nM on aromatase) have been identified.


Assuntos
Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Neoplasias da Mama/enzimologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
6.
J Med Chem ; 65(12): 8345-8379, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35500094

RESUMO

Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor 40 (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of 40 in a clinical study is discussed.


Assuntos
Antineoplásicos , Fosfatidilinositol 3-Quinases , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Compostos Orgânicos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
7.
Mol Cancer Res ; 7(4): 601-13, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19372588

RESUMO

Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein kinase pathways are often constitutively activated in melanoma and have thus been considered as promising drug targets. Exposure of melanoma cells to NVP-BAG956, NVP-BBD130, and NVP-BEZ235, a series of novel, potent, and stable dual PI3K/mammalian target of rapamycin (mTOR) inhibitors, resulted in complete G1 growth arrest, reduction of cyclin D1, and increased levels of p27(KIP1), but negligible apoptosis. In contrast, treatment of melanoma with the pan-class I PI3K inhibitor ZSTK474 or the mTORC1 inhibitor rapamycin resulted only in minor reduction of cell proliferation. In a syngeneic B16 mouse melanoma tumor model, orally administered NVP-BBD130 and NVP-BEZ235 efficiently attenuated tumor growth at primary and lymph node metastatic sites with no obvious toxicity. Metastatic melanoma in inhibitor-treated mice displayed reduced numbers of proliferating and significantly smaller tumor cells. In addition, neovascularization was blocked and tumoral necrosis increased when compared with vehicle-treated mice. In conclusion, compounds targeting PI3K and mTOR simultaneously were advantageous to attenuate melanoma growth and they develop their potential by targeting tumor growth directly, and indirectly via their interference with angiogenesis. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential in metastatic melanoma therapy.


Assuntos
Imidazóis/farmacologia , Melanoma Experimental/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Quinases/metabolismo , Quinolinas/farmacologia , Sirolimo/farmacologia , Triazinas/farmacologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Administração Oral , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose/fisiologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Serina-Treonina Quinases TOR , Células Tumorais Cultivadas
8.
Oncotarget ; 11(11): 956-968, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32215184

RESUMO

The histone 3 lysine 79 (H3K79) methyltransferase (HMT) DOT1L is known to play a critical role for growth and survival of MLL-rearranged leukemia. Serendipitous observations during high-throughput drug screens indicated that the use of DOT1L inhibitors might be expandable to multiple myeloma (MM). Through pharmacologic and genetic experiments, we could validate that DOT1L is essential for growth and viability of a subset of MM cell lines, in line with a recent report from another team. In vivo activity against established MM xenografts was observed with a novel DOT1L inhibitor. In order to understand the molecular mechanism of the dependency in MM, we examined gene expression changes upon DOT1L inhibition in sensitive and insensitive cell lines and discovered that genes belonging to the endoplasmic reticulum (ER) stress pathway and protein synthesis machinery were specifically suppressed in sensitive cells. Whole-genome CRISPR screens in the presence or absence of a DOT1L inhibitor revealed that concomitant targeting of the H3K4me3 methyltransferase SETD1B increases the effect of DOT1L inhibition. Our results provide a strong basis for further investigating DOT1L and SETD1B as targets in MM.

9.
Biochem Soc Trans ; 37(Pt 1): 265-72, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19143644

RESUMO

In contrast with cytotoxic agents that do not differentiate between normal proliferating and tumour cells, targeted therapies primarily exert their actions in cancer cells. Initiation and maintenance of tumours are due to genetic alterations in specific loci. The identification of the genes in which these alterations occur has opened new opportunities for cancer treatment. The PI3K (phosphoinositide 3-kinase) pathway is often overactive in human cancers, and various genetic alterations have been found to cause this. In all cases, PI3K inhibition is considered to be one of the most promising targeted therapies for cancer treatment. The present mini-review provides an update on new PI3K inhibitors currently in or entering clinical development. Recent discoveries, challenges and future prospects will be discussed.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Permeabilidade Capilar/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Inibidores de Proteínas Quinases/química , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR
10.
Mol Cancer Ther ; 7(7): 1851-63, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18606717

RESUMO

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Quinolinas/farmacologia , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto
11.
ACS Med Chem Lett ; 10(12): 1655-1660, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31857842

RESUMO

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

12.
Bioorg Med Chem Lett ; 18(3): 1027-30, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18248814

RESUMO

Imidazo[4,5-c]quinoline derivatives have been discovered and developed as potent and effective modulators of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway to lead to clinical development candidates. The SAR data of representative examples of this compound class and their biological profiling in cellular and in vivo settings are presented and discussed.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Imidazóis/química , Camundongos , Camundongos Nus , Estrutura Molecular , Quinolinas/química , Relação Estrutura-Atividade
13.
ACS Med Chem Lett ; 8(3): 338-343, 2017 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-28337327

RESUMO

Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor.

14.
ACS Med Chem Lett ; 7(8): 730-4, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563394

RESUMO

Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.

15.
ACS Med Chem Lett ; 7(8): 735-40, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563395

RESUMO

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.

16.
ACS Med Chem Lett ; 7(8): 762-7, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27563400

RESUMO

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

17.
Curr Med Chem Anticancer Agents ; 5(5): 449-62, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16178772

RESUMO

A substantial number of experimental and epidemiological studies support an important role for the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway in the biology of human cancers. Components of this signaling cascade have been found to be deregulated in a wide range of solid tumors and hematologic malignancies, and extensive anti-cancer therapeutic programs are now devoted to the identification of agents that specifically block this molecular pathway. This article focuses on the current knowledge of the alterations of the PI3K/PKB pathway in cancer cells and ongoing drug discovery efforts to therapeutically target it. Particular emphasis is placed on medicinal chemistry activities to identify and develop compounds able to modulate the kinase activity of its main molecular components.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Relação Estrutura-Atividade
18.
J Mol Biol ; 320(2): 237-47, 2002 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-12079382

RESUMO

All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen (PBG) as a common precursor. Porphobilinogen synthase (PBGS) synthesizes PBG through the asymmetric condensation of two molecules of aminolevulinic acid (ALA). Crystal structures of PBGS from various sources confirm the presence of two distinct binding sites for each ALA molecule, termed A and P. We have solved the structure of the active-site variant D139N of the Mg2+-dependent PBGS from Pseudomonas aeruginosa in complex with the inhibitor 5-fluorolevulinic acid at high resolution. Uniquely, full occupancy of both substrate binding sites each by a single substrate-like molecule was observed. Both inhibitor molecules are covalently bound to two conserved, active-site lysine residues, Lys205 and Lys260, through Schiff bases. The active site now also contains a monovalent cation that may critically enhance enzymatic activity. Based on these structural data, we postulate a catalytic mechanism for P. aeruginosa PBGS initiated by a C-C bond formation between A and P-side ALA, followed by the formation of the intersubstrate Schiff base yielding the product PBG.


Assuntos
Ácido Aminolevulínico/química , Ácidos Levulínicos/química , Sintase do Porfobilinogênio/química , Pseudomonas aeruginosa/enzimologia , Sequência de Bases , Sítios de Ligação , Catálise , Cátions , Cristalografia por Raios X , Ácidos Levulínicos/metabolismo , Lisina/química , Magnésio/farmacologia , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Ligação Proteica
19.
ChemMedChem ; 10(11): 1884-91, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26381451

RESUMO

Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Geraniltranstransferase/antagonistas & inibidores , Quinolinas/farmacologia , Ácido Salicílico/farmacologia , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Geraniltranstransferase/metabolismo , Humanos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Ácido Salicílico/síntese química , Ácido Salicílico/química , Relação Estrutura-Atividade
20.
Future Med Chem ; 1(1): 137-55, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21426073

RESUMO

BACKGROUND: Among promising targeted therapies for cancer treatment, phosphatidylinositol 3-kinase pathway inhibitors have in the last 3 years continued to retain the attention of both academic institutions and pharmaceutical companies. The large amount of published clinical and preclinical data has indeed confirmed the preponderant role of this so-called survival pathway for tumor maintenance. DISCUSSION: Global efforts have, therefore, been deployed that have led to the genesis of a panoply of small molecule inhibitors. This review will focus on updating the reader on the current medicinal chemistry efforts targeting this pathway. CONCLUSIONS: Recent discoveries important for patient stratification, quantification of target modulation in humans and combination therapies will be presented and discussed.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Regulação Alostérica , Antineoplásicos/química , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo
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