Discovery Or Development High Quality
The Cancer Target Discovery and Development (CTD) Network, a functional genomics initiative, bridges the gap between genomics and development of effective therapeutics. The Network aims to understand tumor development, heterogeneity, drug resistance, and metastasis to develop optimal combinations of chemotherapy with immunotherapy.
Discovery or development
Medicinal chemists identify or generate novel chemical entities that may serve as potential lead molecules for the drug discovery process. These chemists also work to develop strategies and tools for assessing drug consumption and metabolism.
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
There are a number of barriers to the development of immunotherapies for childhood cancers. Unlike many adult tumors, many childhood cancers express few or no markers that can be recognized by the immune system. Similarly, many immunotherapies target specific markers that are expressed in adult cancers but not childhood cancers. Also, tumors that develop in children can develop microenvironments that suppress the immune system and reduce the effectiveness of immunotherapies.
The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.
This article overviews the biology of VEGF, and then focuses on the path from the identification of VEGF and the establishment of its key role in tumour angiogenesis to the clinical development of the humanized anti-VEGF monoclonal antibody bevacizumab.
The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.
Setting up drug discovery and development programs in academic, non-profit and other life science research companies requires careful planning. This chapter contains guidelines to develop therapeutic hypotheses, target and pathway validation, proof of concept criteria and generalized cost analyses at various stages of early drug discovery. Various decision points in developing a New Chemical Entity (NCE), description of the exploratory Investigational New Drug (IND) and orphan drug designation, drug repurposing and drug delivery technologies are also described and geared toward those who intend to develop new drug discovery and development programs.
As universities begin to focus on commercializing research, there is an evolving paradigm for drug discovery and early development focused innovation within the academic enterprise. The innovation process -- moving from basic research to invention and to commercialization and application -- will remain a complex and costly journey. New funding mechanisms, the importance of collaborations within and among institutions, the essential underpinnings of public-private partnerships that involve some or all sectors, the focus of the new field of regulatory science, and new appropriate bridges between federal health and regulatory agencies all come to bear in this endeavor.
We developed these guidelines to assist academic researchers, collaborators and start-up companies in advancing new therapies from the discovery phase into early drug development, including evaluation of therapies in human and/or clinical proof of concept. This chapter outlines necessary steps required to identify and properly validate drug targets, define the utility of employing probes in the early discovery phase, medicinal chemistry, lead optimization, and preclinical proof of concept strategies, as well as address drug delivery needs through preclinical proof of concept. Once a development candidate has been identified, the guidelines provide an overview of human and/or clinical proof of concept enabling studies required by regulatory agencies prior to initiation of clinical trials. Additionally, the guidelines help to ensure quality project plans are developed and projects are advanced consistently. We also outline the expected intellectual property required at key decision points and the process by which decisions may be taken to move a project forward.
The scope of drug discovery and early drug development within the scope of these guidelines spans target identification through human (Phase I) and/or clinical (Phase IIa) proof of concept. This chapter describes an approach to drug discovery and development for the treatment, prevention, and control of cancer. The guidelines and decision points described herein may serve as the foundation for collaborative projects with other organizations in multiple therapeutic areas.
The submission of regulatory documents, for the purpose of this example, reflects the preparation of an Investigational New Drug (IND) application in Common Technical Document (CTD) format. The CTD format is required for preparation of regulatory documents in Europe (according to the Investigational Medicinal Product Dossier [IMPD]), Canada for investigational applications (Clinical Trial Application) and is accepted by the United States Food and Drug Administration (FDA) for INDs. The CTD format is required for electronic CTD (eCTD) submissions. The advantages of the CTD are that it facilitates global harmonization and lays the foundation upon which the marketing application can be prepared. The sections of the CTD are prepared early in development (at the IND stage) and are then updated, as needed, until submission of the marketing application.
Target-based drug discovery begins with identifying the function of a possible therapeutic target and its role in the disease (2). There are two criteria that justify advancement of a project beyond target identification. These are:
An optimized chemical lead is a molecule that will enter IND-enabling GLP studies and GMP supplies will be produced for clinical trials. We will describe the activities that support GLP and GMP development in the next section. This section focuses on the decision process to identify those molecules (Note: projects at this stage may be eligible for Phase II SBIR). Criteria for selecting optimized candidates are listed below: