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1.
Mol Cancer Ther ; 18(12): 2207-2219, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31530649

RESUMO

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.


Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Mitose/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Células HeLa , Humanos , Masculino
2.
Cancer Discov ; 9(2): 248-263, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30373917

RESUMO

Loss-of-function mutations in the retinoblastoma gene RB1 are common in several treatment-refractory cancers such as small-cell lung cancer and triple-negative breast cancer. To identify drugs synthetic lethal with RB1 mutation (RB1 mut), we tested 36 cell-cycle inhibitors using a cancer cell panel profiling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest RB1 association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against RB1 mut cancer cells and leads to durable regression of RB1 mut tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identification of a synthetic lethal interaction between RB1 and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-deficient malignancies, including patients progressing on CDK4/6 inhibitors.See related commentary by Dick and Li, p. 169.This article is highlighted in the In This Issue feature, p. 151.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas de Ligação a Retinoblastoma/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Proteínas de Ligação a Retinoblastoma/genética , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
ACS Med Chem Lett ; 9(6): 557-562, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29937982

RESUMO

The KRASG12C protein product is an attractive, yet challenging, target for small molecule inhibition. One option for therapeutic intervention is to design small molecule ligands capable of binding to and inactivating KRASG12C via formation of a covalent bond to the sulfhydryl group of cysteine 12. In order to better understand the cellular off-target interactions of Compound 1, a covalent KRASG12C inhibitor, we have completed a series of complementary chemical proteomics experiments in H358 cells. A new thiol reactive probe (TRP) was designed and used to construct a cellular target occupancy assay for KRASG12C. In addition, the thiol reactive probes allowed us to profile potential off-target interactions of Compound 1 with over 3200 cysteine residues. In order to complement the TRP data we designed Compound 2, an alkyne containing version of Compound 1, to serve as bait in competitive chemical proteomics experiments. Herein, we describe and compare data from both the TRP and the click chemistry probe pull down experiments.

4.
Mol Cancer Ther ; 15(10): 2344-2356, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27439478

RESUMO

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2-7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344-56. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Modelos Moleculares , Conformação Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ligação Proteica , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Invest New Drugs ; 30(3): 936-49, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21360050

RESUMO

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.


Assuntos
Acetanilidas/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetanilidas/síntese química , Acetanilidas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Cães , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética
6.
Bioorg Med Chem Lett ; 14(12): 3099-102, 2004 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15149652

RESUMO

The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2 receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent compound reported has EC(50)=14 nM.


Assuntos
Piridinas/química , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/química , Animais , Piridinas/sangue , Piridinas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/sangue , Sulfonamidas/farmacologia
7.
Org Lett ; 4(9): 1539-42, 2002 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-11975623

RESUMO

[structure: see text]. A partial stereochemical assignment of quartromicins A3 (R = alpha-D-galactosyl) and D3 (R = H, M+ = Na+, K+, Ca+) is presented.


Assuntos
Furanos/química , Compostos de Espiro/química , Actinomycetales/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estereoisomerismo
8.
Org Lett ; 4(9): 1543-6, 2002 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-11975624

RESUMO

[reaction: see text]. Diastereoselective syntheses of the endo- and exo-spirotetronates 1 and 2, corresponding to the galacto and agalacto fragments of quartromicins A3 and D3, are described. The key step of these syntheses are highly enantio- and diastereoselective Lewis acid catalyzed Diels-Alder reactions of the 1,1,3,4-tetrasubstituted diene 3.


Assuntos
Furanos/síntese química , Compostos de Espiro/síntese química , Catálise , Conformação Molecular , Estereoisomerismo
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