RESUMO
Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Tirosina Quinase da Agamaglobulinemia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Xenoenxertos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
Inhibition of integrin α5ß1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5ß1 by backbone replacement of known αvß1 integrin inhibitors. These integrin α5ß1 inhibitors also retain the nanomolar potency against αvß1 integrin, which shows promise for developing dual integrin α5ß1/αvß1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvß3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5ß1 inhibitors as potential novel asthma therapeutics.
Assuntos
Adamantano/farmacologia , Integrina alfa5beta1/antagonistas & inibidores , Receptores de Vitronectina/antagonistas & inibidores , Hipersensibilidade Respiratória/tratamento farmacológico , Adamantano/química , Animais , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
Assuntos
Flúor/química , Flúor/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.
Assuntos
Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de SinaisRESUMO
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Assuntos
Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , RatosRESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinolinas/química , Semicarbazidas/química , Tioureia/análogos & derivados , Animais , Cães , Feminino , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Quinase I-kappa B/metabolismo , Macaca mulatta , Masculino , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinéticaRESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Semicarbazidas/química , Animais , Cães , Feminino , Ensaios de Triagem em Larga Escala , Quinase I-kappa B/metabolismo , Masculino , Microssomos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-AtividadeRESUMO
One small molecule inhibitor of αvß1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvß1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvß1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvß1 integrin inhibitors as antifibrotics.
RESUMO
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Isoquinolinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismoRESUMO
Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
Assuntos
Inibidores Enzimáticos/síntese química , Indóis/síntese química , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Indóis/química , Injeções Intravenosas , Proteína Quinase 14 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/química , Modelos Moleculares , Ligação Proteica , Isoformas de Proteínas , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Morfolinas/síntese química , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Indicadores e Reagentes , Camundongos , Modelos Moleculares , Conformação Molecular , Morfolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Piperidonas/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Animais , Neoplasias Ósseas/tratamento farmacológico , Ácidos Carboxílicos/química , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Humanos , Ligação de Hidrogênio , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Osteossarcoma/tratamento farmacológico , Piperidonas/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Descoberta de Drogas , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Humanos , Modelos Moleculares , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Piperidonas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Administração Oral , Antineoplásicos/química , Disponibilidade Biológica , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Piperidonas/química , Conformação ProteicaRESUMO
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.