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1.
Bioconjug Chem ; 35(2): 140-146, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38265691

RESUMO

Antibody-drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader, are an emerging area in the field. Herein we describe our efforts of delivering a Bruton's tyrosine kinase (BTK) bifunctional degrader 1 via a CD79b mAb (monoclonal antibody) where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb. The resulting CD79b ADCs, 3 and 4, exhibit in vitro degradation and cytotoxicity comparable with that of 1, and ADC 3 can achieve more sustained in vivo degradation than intravenously administered 1 with markedly reduced systemic exposure of the payload.


Assuntos
Imunoconjugados , Imunoconjugados/química , Tirosina Quinase da Agamaglobulinemia , Anticorpos Monoclonais/química
2.
J Med Chem ; 63(23): 14885-14904, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33258605

RESUMO

Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.


Assuntos
Cicloexanóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Linhagem Celular Tumoral , Cicloexanóis/síntese química , Cicloexanóis/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Relação Estrutura-Atividade
3.
J Med Chem ; 63(5): 2013-2027, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31059256

RESUMO

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.


Assuntos
Antineoplásicos/química , Descoberta de Drogas/métodos , Mutação/genética , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Descoberta de Drogas/tendências , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Acoplamento Molecular/tendências , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
J Med Chem ; 60(12): 4869-4881, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28557458

RESUMO

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.


Assuntos
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Quinases raf/antagonistas & inibidores , Proteínas ras/genética , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Cristalografia por Raios X , Cães , Desenho de Fármacos , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Bioorg Med Chem Lett ; 26(9): 2328-32, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26995528

RESUMO

The Pim proteins (1, 2 and 3) are serine/threonine kinases that have been found to be upregulated in many hematological malignancies and solid tumors. As a result of overlapping functions among the three isoforms, inhibition of all three Pim kinases has become an attractive strategy for cancer therapy. Herein we describe our efforts in identifying potent pan-PIM inhibitors that are derived from our previously reported pyridyl carboxamide scaffold as part of a medicinal chemistry strategy to address metabolic stability.


Assuntos
Amidas/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Amidas/química , Cristalografia por Raios X , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 26(3): 742-746, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26774655

RESUMO

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Xenoenxertos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
7.
PLoS One ; 10(11): e0142741, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26555723

RESUMO

Toll-like receptors (TLRs) are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a downstream signaling cascade. The CD180/MD1 molecular complex is an unusual member of the TLR family, since it lacks the components that are normally required for signal transduction by other TLRs. Therefore the CD180/MD 1 complex has been considered of being incapable of independently initiating cellular signals. Using chemogenetic approaches we identified specifically the membrane bound long form of PIM-1 kinase, PIM-1L as the mediator of CD180-dependent signaling. A dominant negative isoform of PIM-1L, but not of other PIM kinases, inhibited signaling elicited by cross-linking of CD180, and this effect was phenocopied by PIM inhibitors. PIM-1L was directed to the cell membrane by its N-terminal extension, where it colocalized and physically associated with CD180. Triggering CD180 also induced increased phosphorylation of the anti-apoptotic protein BAD in a PIM kinase-dependent fashion. Also in primary human B cells, which are the main cells expressing CD180 in man, cross-linking of CD180 by monoclonal antibodies stimulated cell survival and proliferation that was abrogated by specific inhibitors. By associating with PIM-1L, CD180 can thus obtain autonomous signaling capabilities, and this complex is then channeling inflammatory signals into B cell survival programs. Pharmacological inhibition of PIM-1 should therefore provide novel therapeutic options in diseases that respond to innate immune stimulation with subsequently increased B cell activity, such as lupus erythematosus or myasthenia gravis.


Assuntos
Antígenos CD/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Transdução de Sinais , Linhagem Celular , Proliferação de Células , Citocinas/metabolismo , Humanos , Fosforilação
8.
J Med Chem ; 58(21): 8373-86, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26505898

RESUMO

Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Ácidos Picolínicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/uso terapêutico , Animais , Linhagem Celular Tumoral , Halogenação , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Modelos Moleculares , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo
9.
Clin Cancer Res ; 20(7): 1834-45, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24474669

RESUMO

PURPOSE: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies. EXPERIMENTAL DESIGN: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context. RESULTS: LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model. CONCLUSIONS: We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.


Assuntos
Neoplasias Hematológicas/terapia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas/genética , Animais , Linhagem Celular Tumoral , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Camundongos , Fosforilação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
ACS Med Chem Lett ; 4(12): 1193-7, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900629

RESUMO

Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.

11.
Bioorg Med Chem Lett ; 21(21): 6366-9, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21945284

RESUMO

A series of novel 3,5-disubstituted indole derivatives as potent and selective inhibitors of all three members of the Pim kinase family is described. High throughput screen identified a pan-Pim kinase inhibitor with a promiscuous scaffold. Guided by structure-based drug design, SAR of the series afforded a highly selective indole chemotype that was further developed into a potent set of compounds against Pim-1, 2, and 3 (Pim-1 and Pim-3: IC(50)≤2nM and Pim-2: IC(50)≤100nM).


Assuntos
Descoberta de Drogas , Indóis/química , Indóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Moleculares , Relação Estrutura-Atividade
12.
ACS Med Chem Lett ; 2(1): 34-8, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900252

RESUMO

Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties. A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered. Within this series a compound, 17, was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.

13.
ACS Med Chem Lett ; 2(10): 774-9, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900266

RESUMO

Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.

14.
Bioorg Med Chem ; 14(16): 5592-604, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16697203

RESUMO

A novel series of C(12) ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C(12) modification involves replacing the natural C(12) methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C(12) ethyl macrolide core, a series of C(12) ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C(12) ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C(12) ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.


Assuntos
Antibacterianos/farmacologia , Eritromicina/farmacologia , Cetolídeos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Eritromicina/análogos & derivados , Eritromicina/síntese química , Cetolídeos/síntese química , Metilação , Camundongos , Testes de Sensibilidade Microbiana , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Ribossomos/metabolismo , Relação Estrutura-Atividade
15.
J Med Chem ; 49(5): 1730-43, 2006 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-16509588

RESUMO

A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.


Assuntos
Antibacterianos/síntese química , Cetolídeos/síntese química , Compostos de Vinila/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Disponibilidade Biológica , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Infecções por Haemophilus/tratamento farmacológico , Haemophilus influenzae/efeitos dos fármacos , Meia-Vida , Cetolídeos/farmacocinética , Cetolídeos/farmacologia , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos de Vinila/farmacocinética , Compostos de Vinila/farmacologia
16.
J Org Chem ; 61(2): 775-777, 1996 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-11667004
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