ABSTRACT
INTRODUCTION: SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer. AREAS COVERED: The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated. EXPERT OPINION: SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.
Subject(s)
Antineoplastic Agents , DNA Helicases , Neoplasms , Nuclear Proteins , Patents as Topic , Synthetic Lethal Mutations , Transcription Factors , Humans , Transcription Factors/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/metabolism , Nuclear Proteins/antagonists & inhibitors , Animals , DNA Helicases/metabolism , Antineoplastic Agents/pharmacology , Proteolysis/drug effects , Histone Acetyltransferases/metabolism , Histone Acetyltransferases/antagonists & inhibitors , Molecular Targeted TherapyABSTRACT
INTRODUCTION: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology. AREAS COVERED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented. EXPERT OPINION: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.
Subject(s)
Antineoplastic Agents , DNA Helicases , Molecular Targeted Therapy , Neoplasms , Nuclear Proteins , Patents as Topic , Transcription Factors , Humans , Transcription Factors/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Antineoplastic Agents/pharmacology , DNA Helicases/metabolism , DNA Helicases/antagonists & inhibitors , DNA Helicases/genetics , Animals , Synthetic Lethal Mutations , Mutation , Adenosine Triphosphatases/metabolismABSTRACT
The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.
Subject(s)
Drug Discovery , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Receptors, CXCR/antagonists & inhibitors , Animals , Drug Delivery Systems , Drug Design , Immunologic Factors/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Signal Transduction , Structure-Activity RelationshipABSTRACT
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , DNA/chemistry , Small Molecule Libraries/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Crystallography, X-Ray , DNA/metabolism , Drug Design , Half-Life , Humans , Hyperoxaluria, Primary/metabolism , Hyperoxaluria, Primary/pathology , Indoles/chemistry , Indoles/metabolism , Male , Mice , Molecular Docking Simulation , Small Molecule Libraries/metabolism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/metabolism , Transaminases/genetics , Transaminases/metabolismABSTRACT
Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening â¼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.
Subject(s)
DNA/chemistry , Estrogen Receptor alpha/metabolism , Small Molecule Libraries/chemistry , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Click Chemistry , DNA/metabolism , Estrogen Antagonists/chemistry , Estrogen Antagonists/metabolism , Estrogen Antagonists/pharmacology , Estrogen Antagonists/therapeutic use , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/genetics , Female , Half-Life , Humans , Indoles/chemistry , Indoles/metabolism , Kinetics , Mice , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.
Subject(s)
AMP-Activated Protein Kinases/drug effects , Enzyme Activators/chemical synthesis , Enzyme Activators/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Animals , Enzyme Activation/drug effects , Enzyme Activators/pharmacokinetics , Humans , Indoles/pharmacokinetics , Intestinal Absorption , Kidney/drug effects , Kidney/enzymology , Male , Models, Molecular , Organic Anion Transporters, Sodium-Independent/metabolism , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives). If the pharmacodynamic response is driven by free plasma concentration of the drug then extending the plasma drug concentration is a valid approach. Half-life is dependent on the volume of distribution, which in turn can be dependent upon the ionization state of the molecule. Basic compounds tend to have a higher volume of distribution leading to longer half-lives. However, it has been shown that bases may also have higher promiscuity. In this work, we describe an analysis of in vitro pharmacological profiling and toxicology data investigating the role of primary, secondary, and tertiary amines in imparting promiscuity and thus off-target toxicity. Primary amines are found to be less promiscuous in in vitro assays and have improved profiles in in vivo toxicology studies compared to secondary and tertiary amines.
Subject(s)
Amines/chemistry , Amines/metabolism , Amines/pharmacokinetics , Amines/toxicity , Cell Survival/drug effects , Drug Discovery , ERG1 Potassium Channel/chemistry , ERG1 Potassium Channel/metabolism , Half-Life , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Protein Binding , Structure-Activity RelationshipABSTRACT
Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc.2007, 6, 881; (b) Annu. Rep. Med. Chem.2010, 45, 380).
Subject(s)
Amides/pharmacology , Receptors, Prostaglandin E, EP3 Subtype/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The endocrine hormone glucagon stimulates hepatic glucose output via its action at the glucagon receptor (GCGr) in the liver. In the diabetic state, dysregulation of glucagon secretion contributes to abnormally elevated hepatic glucose output. The inhibition of glucagon-induced hepatic glucose output via antagonism of the GCGr using small-molecule ligands is a promising mechanism for improving glycemic control in the diabetic state. Clinical data evaluating the therapeutic potential of small-molecule GCGr antagonists is currently emerging. Recently disclosed clinical data demonstrates the potential efficacy and possible therapeutic limitations of small-molecule GCGr antagonists. Recent pre-clinical work on the development of GCGr antagonists is also summarized.
Subject(s)
Receptors, Glucagon/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Molecular Structure , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
The central melanocortin system and particularly the melanocortin-4 receptor (MC4R) subtype, plays an important role in the regulation of body weight. The discovery of orally active MC4R agonists suitable for evaluation in human clinical trials as weight loss agents has attracted considerable interest over the past decade, but has proved challenging, in part because of cardiovascular and behavioral side effects. Currently, the only MC4R agonist in clinical trials is a peptide identified as RM-493. To avoid some of the undesirable side effects associated with MC4R activation, new pharmacological approaches for modulating the MC system have been investigated. In this article, we provide a review of the MC4R patent landscape from 2008 to 2014 and analyze the physicochemical properties of compounds described herein.
Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/metabolism , Animals , Humans , Obesity/metabolism , Patents as TopicABSTRACT
Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.
Subject(s)
Benzamides/chemistry , Pyrimidines/chemistry , Receptors, Glucagon/antagonists & inhibitors , Administration, Intravenous , Administration, Oral , Animals , Benzamides/pharmacokinetics , Benzamides/pharmacology , Cells, Cultured , Dogs , Ligands , Molecular Conformation , Molecular Structure , Oxidation-Reduction , Protein Binding/drug effects , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Wistar , StereoisomerismABSTRACT
A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Design , Propionates/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Chemistry, Physical , Dogs , Dose-Response Relationship, Drug , Epithelial Cells/drug effects , Haplorhini , Humans , Liver/cytology , Mice , Molecular Structure , Propionates/administration & dosage , Propionates/chemical synthesis , Rats , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemical synthesis , Structure-Activity RelationshipABSTRACT
Orphan G protein-coupled receptors (oGPCRs) are a class of integral membrane proteins for which endogenous ligands or transmitters have not yet been discovered. Transgenic animal technologies have uncovered potential roles for many of these oGPCRs, providing new targets for the treatment of various diseases. Understanding signaling pathways of oGPCRs and validating these receptors as potential drug targets requires the identification of chemical probe compounds to be used in place of endogenous ligands to interrogate these receptors. A novel chemical probe identification platform was created in which GPCR-focused libraries were screened against sets of oGPCR targets, with a goal of discovering fit-for-purpose chemical probes for the more druggable members of the set. Application of the platform to a set of oGPCRs resulted in the discovery of the first reported small molecule agonists for GPR39, a receptor implicated in the regulation of insulin secretion and preservation of beta cells in the pancreas. Compound 1 stimulated intracellular calcium mobilization in recombinant and native cells in a GPR39-specific manner but did not potentiate glucose-stimulated insulin secretion in human islet preparations.
ABSTRACT
A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.
Subject(s)
Diabetes Mellitus/drug therapy , Pyrazoles/chemistry , Receptors, Glucagon/antagonists & inhibitors , Animals , Chemistry, Pharmaceutical/methods , Dogs , Dose-Response Relationship, Drug , Drug Design , Ether/chemistry , Glucagon/chemistry , Glucose/chemistry , Humans , Kinetics , Models, Chemical , Molecular Weight , Rats , TemperatureABSTRACT
A highly selective, radical-mediated (4 + 2) coupling reaction of aldehydes and conjugated olefins has been achieved through asymmetric SOMO-catalysis. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnishes a cation which is vulnerable to nucleophilic addition. A range of aromatic aldehydes are shown to couple with styrenes and dienes to provide cyclic products with high chemical efficiency, regioselectivity, and stereoselectivity.
Subject(s)
Aldehydes/chemistry , Alkenes/chemistry , Biological Products/chemistry , Catalysis , Cyclohexanes/chemistry , Kinetics , Stereoisomerism , Substrate SpecificityABSTRACT
The preparation of thiolane 1-oxide 10 by photochemically mediated rearrangement of sulfoxide 9 in high yield is described. The efficient construction of quaternary carbon centers underscores the utility of this methodology in organic synthesis. Further manipulation of photoadduct 10 leads to the formation of diverse heterocyclic structures.
Subject(s)
Photochemistry/methods , Sulfhydryl Compounds/chemical synthesis , Molecular StructureABSTRACT
[reaction: see text] Pauson-Khand cyclization of dioxanone photoadduct 21 leads to the formation of a single product in good yield. However, retro-aldol fragmentation of the pentacyclic cyclopentenone 22 leads to the formation of 23, with cis C-8/C-10 intrabridgehead stereochemistry, unlike the target compound ingenol 1, which possesses C-8/C-10 trans intrabridgehead stereochemistry.