ABSTRACT
The 'Therapeutics discovery: From bench to first in-human trials' conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10-12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China. The program was divided into two parts. A pre-symposium day took place on October 10, during which courses were conducted on clinical trials, preclinical drug discovery, molecular biology and nanofiber research. The attendees had the opportunity for one-to-one meetings with international experts to exchange information and foster collaborations. In the second part of the conference, which took place on October 11 and 12, the clinical trials pipeline, design and recruitment of volunteers, and economic impact of clinical trials were discussed. The Saudi Food and Drug Administration presented the regulations governing clinical trials in the KSA. The process of preclinical drug discovery from small molecules, cellular and immunologic therapies, and approaches to identifying new targets were also presented. The recommendation of the conference was that researchers in the KSA must invest more fund, talents and infrastructure to lead the region in phase I clinical trials and preclinical drug discovery. Diseases affecting the local population, such as Middle East Respiratory Syndrome and resistant bacterial infections, represent the optimal starting point.
ABSTRACT
The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Modification Methylases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Hematologic Neoplasms/drug therapy , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Crystallography, X-Ray , DNA Modification Methylases/chemistry , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Epigenesis, Genetic/drug effects , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Histocompatibility Antigens/chemistry , Histocompatibility Antigens/genetics , Histocompatibility Antigens/metabolism , Histone-Lysine N-Methyltransferase/chemistry , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Humans , Interferons/immunology , Interferons/metabolism , Mice , Mice, Inbred BALB C , Microsomes, Liver , Molecular Docking Simulation , Survival Analysis , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30â¯000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding.
Subject(s)
Benzamides/pharmacology , Drug Evaluation, Preclinical/methods , Hemorrhage/prevention & control , Hemostatics/chemistry , Hemostatics/pharmacology , Hydroxamic Acids/pharmacology , Animals , Antifibrinolytic Agents/chemistry , Antifibrinolytic Agents/pharmacology , Benzamides/chemistry , Caco-2 Cells/drug effects , Drug Discovery/methods , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Hemorrhage/drug therapy , Hemorrhage/metabolism , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 10/metabolism , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacology , Mice, Inbred C57BL , Molecular Structure , Molecular Targeted Therapy/methodsABSTRACT
Here we report the development and validation of a complete solution to manage and analyze the data produced by image-based phenotypic screening campaigns of small-molecule libraries. In one step initial crude images are analyzed for multiple cytological features, statistical analysis is performed and molecules that produce the desired phenotypic profile are identified. A naïve Bayes classifier, integrating chemical and phenotypic spaces, is built and utilized during the process to assess those images initially classified as "fuzzy"-an automated iterative feedback tuning. Simultaneously, all this information is directly annotated in a relational database containing the chemical data. This novel fully automated method was validated by conducting a re-analysis of results from a high-content screening campaign involving 33 992 molecules used to identify inhibitors of the PI3K/Akt signaling pathway. Ninety-two percent of confirmed hits identified by the conventional multistep analysis method were identified using this integrated one-step system as well as 40 new hits, 14.9% of the total, originally false negatives. Ninety-six percent of true negatives were properly recognized too. A web-based access to the database, with customizable data retrieval and visualization tools, facilitates the posterior analysis of annotated cytological features which allows identification of additional phenotypic profiles; thus, further analysis of original crude images is not required.
Subject(s)
Drug Evaluation, Preclinical/statistics & numerical data , Image Processing, Computer-Assisted/statistics & numerical data , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Cell Line , Database Management Systems , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Signal Transduction/drug effects , Systems BiologyABSTRACT
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
Subject(s)
Amino Acids/pharmacology , Bridged Bicyclo Compounds/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Pyridines/pharmacology , Pyridones/pharmacology , Receptors, Metabotropic Glutamate/agonists , Sulfonamides/pharmacology , Allosteric Regulation , Amino Acids/chemistry , Animals , Bridged Bicyclo Compounds/chemistry , Drug Evaluation, Preclinical , Drug Stability , Excitatory Amino Acid Agonists/chemistry , Excitatory Amino Acid Agonists/classification , Humans , Hydrophobic and Hydrophilic Interactions , Mice , Molecular Structure , Motor Activity/drug effects , Pyridines/chemistry , Pyridones/chemistry , Pyridones/classification , Pyridones/isolation & purification , Recombinant Proteins/drug effects , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The inability of molecules to permeate the BBB is a significant source of attrition in Central Nervous System (CNS) drug discovery. Given the increasing medical drivers for new and improved CNS drugs, small molecule transfer across the BBB is attracting a heightened awareness within pharmaceutical industry and medical fields. In order to assess the potential for small CNS molecules to permeate the BBB, a variety of methods and models, from in silico to in vivo going through in vitro models are developed as predictive tools in drug discovery. This review gives a comprehensive overview of different approaches currently considered in drug discovery to circumvent the lack of small molecule transfer through the BBB, together with their inherent advantages and disadvantages. Particularly, special attention is drawn to in silico models, with a detailed and contemporary point of view on prediction tools and guidelines for rational design.