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1.
PNAS Nexus ; 3(4): pgae153, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38665159

RESUMEN

Damaged DNA-binding protein-1 (DDB1)- and CUL4-associated factor 12 (DCAF12) serves as the substrate recognition component within the Cullin4-RING E3 ligase (CRL4) complex, capable of identifying C-terminal double-glutamic acid degrons to promote the degradation of specific substrates through the ubiquitin proteasome system. Melanoma-associated antigen 3 (MAGEA3) and T-complex protein 1 subunit epsilon (CCT5) proteins have been identified as cellular targets of DCAF12. To further characterize the interactions between DCAF12 and both MAGEA3 and CCT5, we developed a suite of biophysical and proximity-based cellular NanoBRET assays showing that the C-terminal degron peptides of both MAGEA3 and CCT5 form nanomolar affinity interactions with DCAF12 in vitro and in cells. Furthermore, we report here the 3.17 Šcryo-EM structure of DDB1-DCAF12-MAGEA3 complex revealing the key DCAF12 residues responsible for C-terminal degron recognition and binding. Our study provides new insights and tools to enable the discovery of small molecule handles targeting the WD40-repeat domain of DCAF12 for future proteolysis targeting chimera design and development.

2.
J Med Chem ; 66(9): 6239-6250, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37102218

RESUMEN

Proteolysis targeting chimeras (PROTACs), heterobifunctional protein degraders, have emerged as an exciting and transformative technology in chemical biology and drug discovery to degrade disease-causing proteins through co-opting of the ubiquitin-proteasome system (UPS). Here, we develop a mechanistic mathematical model for the use of irreversible covalent chemistry in targeted protein degradation (TPD) either to a target protein of interest (POI) or an E3 ligase ligand, considering the thermodynamic and kinetic factors governing ternary complex formation, ubiquitination, and degradation through the UPS. We highlight key advantages of covalency to the POI and E3 ligase and the underlying theoretical basis in the TPD reaction framework. We further identify regimes where covalency can serve to overcome weak binary binding affinities and improve the kinetics of ternary complex formation and degradation. Our results highlight the enhanced catalytic efficiency of covalent E3 PROTACs and thus their potential to improve the degradation of fast turnover targets.


Asunto(s)
Proteínas , Quimera Dirigida a la Proteólisis , Cinética , Proteínas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitinación , Proteolisis , Termodinámica
3.
ACS Med Chem Lett ; 13(7): 1182-1190, 2022 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-35859867

RESUMEN

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs-with varying length, polarity, and rigidity-were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on "linkerology", and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design-make-test cycles.

4.
J Med Chem ; 65(4): 3518-3538, 2022 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-35108011

RESUMEN

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.


Asunto(s)
Proteínas de la Membrana/agonistas , Animales , Cristalografía por Rayos X , AMP Cíclico/química , AMP Cíclico/farmacología , GMP Cíclico/química , GMP Cíclico/farmacología , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunoterapia/métodos , Proteínas de la Membrana/química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neoplasias/inmunología , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas
5.
Drug Discov Today ; 26(5): 1115-1125, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33497831

RESUMEN

Kinases, accounting for 20% of the human genome, have been the focus of pharmaceutical drug discovery efforts for over three decades. Despite concerns surrounding the tractability of kinases as drug targets, it is evident that kinase drug discovery offers great potential, underscored by the US Food and Drug Administration (FDA) approval of 48 small-molecule kinase inhibitors. Despite these successes, it is challenging to identify novel kinome selective inhibitors with good pharmacokinetic/pharmacodynamic (PK/PD) properties, and resistance to kinase inhibitor treatment frequently arises. A new era of kinase drug discovery predicates the need for diverse and powerful tools to discover the next generation of kinase inhibitors. Here, we outline key tenets of the Bristol Meyers Squibb (BMS) kinase platform, to enable efficient generation of highly optimized kinase inhibitors.


Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/efectos de los fármacos , Animales , Aprobación de Drogas , Resistencia a Medicamentos , Humanos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Quinasas/metabolismo , Estados Unidos , United States Food and Drug Administration
6.
J Immunother Cancer ; 9(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33408094

RESUMEN

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. METHODS: Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. RESULTS: CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. CONCLUSION: CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Ginsenósidos/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Neoplasias Óseas/inmunología , Neoplasias Óseas/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ginsenósidos/farmacología , Humanos , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Sarcoma/inmunología , Sarcoma/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
J Med Chem ; 64(1): 677-694, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33370104

RESUMEN

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.


Asunto(s)
Ciclopropanos/farmacología , Descubrimiento de Drogas , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Animales , Catálisis , Cristalografía por Rayos X , Ciclopropanos/química , Humanos , Ratones , Oxazoles/química , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Psoriasis/tratamiento farmacológico , Relación Estructura-Actividad , TYK2 Quinasa/metabolismo
8.
ACS Med Chem Lett ; 11(3): 266-271, 2020 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-32184955

RESUMEN

Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

9.
J Med Chem ; 62(20): 8953-8972, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31314518

RESUMEN

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.


Asunto(s)
Niacinamida/análogos & derivados , Ácidos Nicotínicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Regulación Alostérica , Animales , Humanos , Ligandos , Ratones , Niacinamida/metabolismo , Niacinamida/farmacología , Ácidos Nicotínicos/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-Actividad
10.
J Med Chem ; 62(20): 8973-8995, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31318208

RESUMEN

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Descubrimiento de Drogas , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Animales , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/uso terapéutico , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico
11.
Sci Transl Med ; 11(502)2019 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-31341059

RESUMEN

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.


Asunto(s)
Autoinmunidad/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , TYK2 Quinasa/química , Animales , Femenino , Voluntarios Sanos , Compuestos Heterocíclicos/farmacología , Humanos , Interferón alfa-2/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores
12.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-30891145

RESUMEN

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

13.
J Med Chem ; 62(7): 3228-3250, 2019 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-30893553

RESUMEN

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Descubrimiento de Drogas , Indoles/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Artritis Reumatoide/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Indoles/farmacocinética , Indoles/uso terapéutico , Concentración 50 Inhibidora , Lupus Eritematoso Sistémico/tratamiento farmacológico , Macaca fascicularis , Ratones , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico
14.
Bioorg Med Chem Lett ; 28(18): 3080-3084, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30097367

RESUMEN

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Carbazoles/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Carbazoles/síntesis química , Carbazoles/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
16.
Anal Biochem ; 497: 8-17, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26743718

RESUMEN

XIAP (X-chromosome-linked inhibitor of apoptosis protein) is a central apoptosis regulator that blocks cell death by inhibiting caspase-3, caspase-7, and caspase-9 via binding interactions with the XIAP BIR2 and BIR3 domains (where BIR is baculovirus IAP repeat). Smac protein, in its dimeric form, effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. Here we describe the development of highly sensitive homogeneous time-resolved fluorescence resonance energy transfer (HTRF) assays to measure binding affinities of potent bivalent peptidomimetic inhibitors of XIAP. Our results indicate that these assays can differentiate Smac-mimetic inhibitors with a wide range of binding affinities down to the picomolar range. Furthermore, we demonstrate the utility of these fluorescent tools for characterization of inhibitor off-rates, which as a crucial determinant of target engagement and cellular potency is another important parameter to guide optimization in a structure-based drug discovery effort. Our study also explores how increased inhibitor valency can lead to enhanced potency at multimeric proteins such as IAP.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia/métodos , Peptidomiméticos/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Animales , Caspasa 3/metabolismo , Línea Celular , Humanos , Ratones Endogámicos BALB C , Peptidomiméticos/química , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteína Inhibidora de la Apoptosis Ligada a X/química
17.
Bioanalysis ; 8(4): 265-74, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26807991

RESUMEN

BACKGROUND: A target protein-based affinity extraction LC-MS/MS method was developed to enable plasma level determination following ultralow dosing (0.1-3 µg/kg) of an inhibitor of apoptosis proteins molecule. Methodology & results: Affinity extraction (AE) utilizing immobilized target protein BIR2/BIR3 was used to selectively capture the inhibitor of apoptosis proteins molecule from dog plasma and enable removal of background matrix components. Pretreatment of plasma samples using protein precipitation was found to provide an additional sensitivity gain. A LLOQ of 7.8 pM was achieved by combining protein precipitation with AE. The method was used to support an ultralow dose dog toxicity study. CONCLUSION: AE-LC-MS/MS, utilizing target protein, is a highly sensitive methodology for small molecule quantification with potential for broader applicability.


Asunto(s)
Análisis Químico de la Sangre/métodos , Fraccionamiento Químico/métodos , Cromatografía Liquida/métodos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Isoquinolinas/análisis , Límite de Detección , Oligopéptidos/análisis , Bibliotecas de Moléculas Pequeñas/análisis , Espectrometría de Masas en Tándem/métodos , Animales , Perros , Femenino , Humanos , Proteínas Inmovilizadas/antagonistas & inhibidores , Proteínas Inmovilizadas/química , Proteínas Inhibidoras de la Apoptosis/química , Isoquinolinas/química , Isoquinolinas/farmacología , Masculino , Oligopéptidos/química , Oligopéptidos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
18.
Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26302264

RESUMEN

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Asunto(s)
Antineoplásicos/farmacología , Transporte Biológico/efectos de los fármacos , Caspasa 3/metabolismo , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Mitocondriales/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Biomimética/métodos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Células HCT116 , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína/efectos de los fármacos
19.
ACS Med Chem Lett ; 6(7): 770-5, 2015 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-26191364

RESUMEN

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

20.
J Med Chem ; 58(3): 1556-62, 2015 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-25584393

RESUMEN

The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Prolina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/patología , Prolina/síntesis química , Prolina/química , Relación Estructura-Actividad
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