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Delivering probes and clinical candidates to test precision medicine therapeutic hypotheses
Author(s) -
Watterson Daniel Martin,
Roy Saktimayee M,
Van Eldik Linda J,
Arancio Ottavio
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.055264
Subject(s) - drug discovery , computational biology , deliverable , clinical trial , pharmacology , drug development , medicine , bioinformatics , drug , neuroscience , biology , management , economics
Background . There is a need for selective clinical candidates that allow testing of explicit precision medicine hypotheses emerging from diverse clinical data acquisition, analysis and archiving initiatives. Candidates that target pathophysiology progression mechanisms would offer the potential for disease modification. Appropriate clinical candidates would, ideally, facilitate clinical hypothesis testing in order to find the right drug at the right dose at the right time for the right patient. In this regard, we developed a discovery and development platform focused on altering pathophysiology progression mechanisms and delivers novel small molecule candidates with good bioavailability, safety profiles and potential for evaluation in proof‐of‐concept clinical trials. Method Synaptic dysfunction and neuroflammation are pathophysiology progression mechanisms. Our discovery starts with molecular scaffolds emerging from pharmacoinformatic analysis of prior CNS drugs and their clinical utility. Medicinal chemistry diversification is driven by chemoinformatics related to small molecule drug properties in biological systems and by pharmacoinformatics related to pharmacology and toxicology potential. Campaigns can target single molecular entities (e.g., a serine/threonine protein kinase), pathways (e.g., cytokine biosynthesis dysfunction) or combinations (e.g., serotonin receptor linked dysfunction). Efficient medicinal chemistry approaches include diversifications based on [Target:Inactive Molecular Fragment] complexes or us of SOSA variations (systematic optimization of side activities). Best‐in‐class candidates emerge from IND‐enabling preclinical safety pharmacology and tractability of GMP production and delivery. Results MW150, MW189 and MW151 are example deliverables that continue to exhibit utility in human subjects. MW150 is a highly selective CNS S/T protein kinase inhibitor deliverable entering phase 2a safety trials for AD patients. MW150 exhibited selectivity in hierarchal kinome‐wide and large scale functional GPCR screens and absence of activity in standardized screens related to ADMET liabilities. Preclinical safety testing according to FDA/ICH guidelines provided the foundation for regulatory approval of clinical trial initiation. MW189 and MW151 are clinical trial stage deliverables where design and synthesis of a curated small chemical library was based on SOSA rationale and functional vetting was based on attenuation of cytokine biosynthesis dysfunction. Conclusion Overall, the platform continues to be validated for delivery of novel small molecule candidates for human studies.