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1.
Mol Cancer Ther ; 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39235218

ABSTRACT

Targeting synthetic lethal interactions between genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay between terminal uridyltransferase 4 (TUT4) and terminal uridyltransferase 7 (TUT7), the 3'-5' exoribonuclease DIS3L2, and the SKI complex-interacting factor Focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency post-transcriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Re-introduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is FOCAD loss-driven. We propose a model where, in absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacological inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.

2.
ACS Med Chem Lett ; 12(10): 1539-1545, 2021 Oct 14.
Article in English | MEDLINE | ID: mdl-34671445

ABSTRACT

SET domain-containing protein 2 (SETD2), a histone methyltransferase, has been identified as a target of interest in certain hematological malignancies, including multiple myeloma. This account details the discovery of EPZ-719, a novel and potent SETD2 inhibitor with a high selectivity over other histone methyltransferases. A screening campaign of the Epizyme proprietary histone methyltransferase-biased library identified potential leads based on a 2-amidoindole core. Structure-based drug design (SBDD) and drug metabolism/pharmacokinetics (DMPK) optimization resulted in EPZ-719, an attractive tool compound for the interrogation of SETD2 biology that enables in vivo target validation studies.

3.
ACS Med Chem Lett ; 11(10): 1899-1904, 2020 Oct 08.
Article in English | MEDLINE | ID: mdl-33062171

ABSTRACT

Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC.

4.
PLoS One ; 13(6): e0197372, 2018.
Article in English | MEDLINE | ID: mdl-29856759

ABSTRACT

A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.


Subject(s)
Adenocarcinoma of Lung/drug therapy , Carcinogenesis/genetics , Histone-Lysine N-Methyltransferase/genetics , A549 Cells , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , CRISPR-Cas Systems , Carcinogenesis/drug effects , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/chemistry , Humans , Methylation/drug effects , Methyltransferases/antagonists & inhibitors , RNA Interference , Small Molecule Libraries/pharmacology
5.
PLoS One ; 13(5): e0197082, 2018.
Article in English | MEDLINE | ID: mdl-29742153

ABSTRACT

WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.


Subject(s)
Enzyme Inhibitors/chemistry , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Neoplasms/drug therapy , Peptides/chemistry , Repressor Proteins/antagonists & inhibitors , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Histone-Lysine N-Methyltransferase/chemistry , Histone-Lysine N-Methyltransferase/genetics , Histones/chemistry , Histones/genetics , Humans , Lysine/chemistry , Neoplasms/enzymology , Norleucine/analogs & derivatives , Norleucine/chemistry , Norleucine/pharmacology , PR-SET Domains/genetics , Peptides/genetics , Protein Conformation/drug effects , Repressor Proteins/chemistry , Repressor Proteins/genetics
6.
Cell Chem Biol ; 24(9): 1120-1147, 2017 Sep 21.
Article in English | MEDLINE | ID: mdl-28938089

ABSTRACT

Comprehensive whole-exome sequencing, DNA copy-number determination, and transcriptomic analyses of diverse cancers have greatly expanded our understanding of the biology of many tumor types. In addition to mutations in the common cell-of-origin specific driver mutations, these studies have also revealed a large number of loss-of-function and gain-of-function mutations in chromatin-modifying proteins (CMPs). This has revealed that epigenetic dysregulation is a common feature of most pediatric and adult cancers. Many specific and potent inhibitors have been developed for multiple CMP classes, which have assisted in elucidating the role of epigenetics as well as epigenetic vulnerabilities in these cancer types. Clinical trials with numerous CMP inhibitors are also currently in progress to evaluate the therapeutic potential of epigenetic inhibitors. In this review, we aim to provide a summary of genetic mutations in epigenetic genes and a review of CMP inhibitors suitable for preclinical studies or currently in clinical trials. Additionally, we highlight the CMPs for which potent inhibitors have not been developed and additional research focus should be dedicated.


Subject(s)
Drug Discovery , Epigenesis, Genetic , Neoplasms/pathology , Acetylation/drug effects , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , Endosomal Sorting Complexes Required for Transport/antagonists & inhibitors , Endosomal Sorting Complexes Required for Transport/genetics , Endosomal Sorting Complexes Required for Transport/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Histones/metabolism , Humans , Methylation/drug effects , Neoplasms/drug therapy , Neoplasms/genetics
7.
Atherosclerosis ; 263: 405-411, 2017 08.
Article in English | MEDLINE | ID: mdl-28549500

ABSTRACT

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.


Subject(s)
Carotid Artery Diseases/etiology , Coronary Artery Disease/etiology , Hyperlipoproteinemia Type II/genetics , Multifactorial Inheritance , Mutation , Polymorphism, Single Nucleotide , Adult , Aged , Asymptomatic Diseases , Biomarkers/blood , Carotid Artery Diseases/blood , Carotid Artery Diseases/diagnostic imaging , Carotid Intima-Media Thickness , Cholesterol, LDL/blood , Computed Tomography Angiography , Coronary Angiography/methods , Coronary Artery Disease/blood , Coronary Artery Disease/diagnostic imaging , DNA Mutational Analysis , England , Female , Genetic Predisposition to Disease , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/drug therapy , Male , Middle Aged , Netherlands , Phenotype , Risk Factors , Severity of Illness Index
8.
Future Med Chem ; 5(17): 2037-56, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24215345

ABSTRACT

BACKGROUND: Recently, we reported ethyl nicotinates as antagonists of the P2Y12 receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis. RESULTS: Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole. CONCLUSION: The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.


Subject(s)
Oxazoles/chemistry , Oxazoles/pharmacology , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/pharmacology , Animals , Humans , Hydrogen Bonding , Microsomes/metabolism , Models, Molecular , Oxazoles/metabolism , Oxazoles/pharmacokinetics , Purinergic P2Y Receptor Antagonists/metabolism , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Rats , Structure-Activity Relationship
9.
Eur J Med Chem ; 65: 360-75, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23747805

ABSTRACT

The present paper describes the development of a new series of P2Y12 receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 µM, aq solubility <0.1 µM, microsomal CLint (HLM) ≥300 µM/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 µM, aq solubility = 90 µM, microsomal CLint (HLM) = 70 µM/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 µM, aq solubility = 83 µM, microsomal CLint (HLM) = 28 µM/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality.


Subject(s)
Nicotinic Acids/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y12/metabolism , Urea/analogs & derivatives , Animals , Molecular Structure , Nicotinic Acids/chemical synthesis , Nicotinic Acids/chemistry , Purinergic P2Y Receptor Antagonists/chemical synthesis , Purinergic P2Y Receptor Antagonists/chemistry , Rats , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacology
10.
Ann Clin Biochem ; 48(Pt 2): 159-65, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21355015

ABSTRACT

BACKGROUND: The Department of Health launched a cardiovascular disease risk assessment initiative with particular reference to reducing health inequalities in ethnic minorities. Collaboration between HEART UK, Royal Free Hampstead NHS Trust and Hindu Temples resulted in vascular screening in North London. METHODS: Subjects of South Asian origin were screened. A full lipid profile and glucose were measured using a point of care testing (POCT) Cholestech LDX analyser (LDX). Venous samples were analysed in our hospital laboratory. RESULTS: The results (215 men; 191 women) were divided into tertiles and Bland-Altman plots were used to assess agreement. At high-density lipoprotein cholesterol (HDL-C) concentrations < 1.0 mmol/L the LDX underestimated values by -0.2 mmol/L (P<0.0001). At HDL-C concentrations >1.3 mmol/L this bias disappeared. For total cholesterol the concentration-dependent negative bias was evident at concentrations of < 4.1 mmol/L (P < 0.0001). This bias was less evident at higher concentrations. A similar pattern was seen for low-density lipoprotein cholesterol. There were also small variations in glucose and triglyceride values. However, there was excellent agreement in calculated cardiovascular disease risk using kappa analysis for JBS2, QRISK2, ETHRISK and Framingham (κ = 0.86, 0.92, 0.94 and 0.88, respectively). This was a high-risk population since 9.7-19.4% had a ≥ 20% 10-y probability of a vascular event depending on the risk engine and assay method used. The corresponding values for intermediate risk (11-19%) were 18.6-25.7%. CONCLUSIONS: There was a minimum mismatch irrespective of the type of risk calculator used. POCT measurements are adequate for the National Health Service Health Check.


Subject(s)
Cardiovascular Diseases/diagnosis , National Health Programs , Point-of-Care Systems , Adult , Aged , Blood Glucose/metabolism , Cardiovascular Diseases/blood , Female , Humans , Laboratories, Hospital , Lipids/blood , Male , Middle Aged , Risk Assessment , United Kingdom
11.
J Med Chem ; 50(4): 607-10, 2007 Feb 22.
Article in English | MEDLINE | ID: mdl-17243660

ABSTRACT

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Bradykinin B1 Receptor Antagonists , Chromans/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , CHO Cells , Capillary Permeability/drug effects , Chlorocebus aethiops , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Cricetulus , Crystallography, X-Ray , Entropy , Humans , In Vitro Techniques , Models, Molecular , Molecular Conformation , Pleurisy/drug therapy , Rabbits , Rats , Species Specificity , Stereoisomerism , Structure-Activity Relationship
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