RESUMEN
This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.
Asunto(s)
Descubrimiento de Drogas , Isoquinolinas/síntesis química , Diseño de Fármacos , Isoquinolinas/química , Estructura MolecularRESUMEN
The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.
Asunto(s)
Neoplasias , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Humanos , Ratones , Animales , Transducción de Señal , Proteínas Tirosina Quinasas Receptoras/metabolismo , Sitio AlostéricoRESUMEN
ß-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase. The fragment hits were identified by using X-ray crystallography and biophysical techniques. This work led to the discovery of a series of compounds that bind GCase with nM potency and positively modulate GCase activity in cells.
Asunto(s)
Sitio Alostérico , Descubrimiento de Drogas , Glucosilceramidasa , Glucosilceramidasa/metabolismo , Glucosilceramidasa/antagonistas & inhibidores , Glucosilceramidasa/química , Humanos , Cristalografía por Rayos X , Relación Estructura-Actividad , Modelos Moleculares , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/metabolismoRESUMEN
A series of C-H functionalisation plate-based chemical screens and other C-H activation protocols were developed for the chemical diversification of drug molecules. In this Letter, metalloporphyrin and other catalytic oxidation systems are described in addition to chlorination. Mifepristone and antalarmin are used as substrates. The products obtained and the biological data demonstrate the potential utility of this approach.
Asunto(s)
Química Farmacéutica/métodos , Mifepristona/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Biomimética , Carbono/química , Cloro/química , Diseño de Fármacos , Humanos , Hidrógeno/química , Concentración 50 Inhibidora , Metaloporfirinas/química , Metales/química , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Oxígeno/química , Relación Estructura-ActividadRESUMEN
Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.
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Acetilmuramil-Alanil-Isoglutamina/farmacología , Compuestos Organometálicos/farmacología , Paladio/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/química , Humanos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
With renewed interest in atropisomerism of drug molecules, efficient methods to experimentally determine torsion rotational energy barriers are needed. Here, we describe use of the chiral phosphoric acid solvating agent (+)-TiPSY to resolve the signals of atropisomers in 19F NMR and to use the data to study the kinetics of racemization and determine the rotational energy barrier of clinical compound MRTX1719. This method is complimentary to traditional chiral high-performance liquid chromatography (HPLC) and enhances the toolkit for chiral analysis techniques.
RESUMEN
Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 IC50 = 7.8 µM), was developed.
Asunto(s)
Proteína Quinasa 1 Activada por Mitógenos , Inhibidores de Proteínas Quinasas , Acrilamidas/química , Adenosina Trifosfato/química , Cristalografía por Rayos X , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Rayos XRESUMEN
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Cristalografía por Rayos X , Perros , Humanos , Indoles/síntesis química , Indoles/metabolismo , Indoles/farmacocinética , Masculino , Ratones Endogámicos BALB C , Proteína Quinasa 1 Activada por Mitógenos/química , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Estructura Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proto-Oncogenes Mas , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
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Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Propionatos/metabolismo , Unión Proteica/efectos de los fármacos , Sitios de Unión , Línea Celular , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/química , Conformación Molecular , Factor 2 Relacionado con NF-E2/química , Propionatos/síntesis química , Propionatos/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A highly selective method to protect the 11 beta-OH position of steroid (1) has been developed. This is achieved via double silyl protection of the 11 beta, 17 alpha-diol, followed by selective desilylation of the 17 alpha-OH under basic conditions without the need for a fluoride source.
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Esteroides/química , Esteroides/síntesis química , Relación Estructura-ActividadRESUMEN
Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).
Asunto(s)
Antineoplásicos/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Piperazinas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Canal de Potasio ERG1/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Macaca fascicularis , Masculino , Ratones Endogámicos BALB C , Piperazinas/química , Piperazinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Proteína Inhibidora de la Apoptosis Ligada a X/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37 degrees C, 10.2 min) to glutarimide 4. Glucuronide 3 was synthesized efficiently via acylation of benzylglucuronate with N-benzyloxymethyl-protected 2. Glucuronide and imide reacted rapidly in aqueous solution, pH 7.4, with amino acids and glutathione to form stable amides and unstable thioesters. Imide 4 acylated eight lysine Nepsilon-amino groups of human serum albumin. Rapid cyclization of 3 was attributed to attack on the ester linkage by an unusually nucleophilic glutaramide NH (pKa in 2 = 9.76). N-propyl 3 was refractory to acyl migration and cyclization. This suggested a synthetic strategy for preparing analogues of 2 that form chemically stable acyl glucuronides.
Asunto(s)
Glucurónidos/química , Neprilisina/antagonistas & inhibidores , Neprilisina/química , Ácidos Pentanoicos/química , Ácidos Pentanoicos/metabolismo , Piperidonas/síntesis química , Tiadiazoles/química , Tiadiazoles/síntesis química , Tiadiazoles/metabolismo , Animales , Ciclización , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Masculino , Piperidonas/química , Piperidonas/farmacocinética , Ratas , Ratas Wistar , Albúmina Sérica/química , Estereoisomerismo , Tiadiazoles/farmacocinéticaRESUMEN
XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.
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Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Piperazinas/química , Piperazinas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Peptidomiméticos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-ActividadRESUMEN
Simply reversing the order of addition of aqueous acid and Et2 O to the Barbier intermediate 1 of the known indium-mediated allylation leads to unprecedented deoxygenative rearrangements [Eq. (a)].
RESUMEN
The nuclear magnetic shieldings of two chloropyrimidine species have been predicted and analyzed by means of ab initio and DFT methods. The results have been compared with the experimental values and with those from other database-related approaches. These dataset-based techniques are found to be particularly valuable because of the accurate and instantaneous prediction of the 13C chemical shifts. On the other hand, only a few quantum chemistry based approaches were showed to be the most precise to predict 1H chemical shifts and to elucidate unequivocally the 1H NMR spectra of the regioisomeric mixture under study. Special emphasis was put on incorporating the solvent effect, implicitly, or explicitly. The influence of the level of theory and basis set in the predicted values has also been discussed.