Frontiers in Pharmacology (Aug 2022)
Phenotypic screening of low molecular weight compounds is rich ground for repurposed, on-target drugs
Abstract
A target-based drug discovery strategy has led to a bias away from low molecular weight (MWT) drug discovery. Analysis of the ACS chemistry registration system shows that most low MWT drugs were first made in the time era before target-based drug discovery. Therapeutic activity among most low MWT drugs was identified in the era of phenotypic drug discovery when drugs were selected based on their phenotypic effects and before in vitro screening, mechanism of action considerations and experiences with fragment screening became known. The common perception that drugs cannot be found among low MWT compounds is incorrect based on both drug discovery history and our own experience with MLR-1023. The greater proportion of low MWT compounds that are commercially available compared to higher MWT compounds is a factor that should facilitate biology study. We posit that low MWT compounds are more suited to identification of new therapeutic activity using phenotypic screens provided that the phenotypic screening method has enough screening capacity. On-target and off-target therapeutic activities are discussed from both a chemistry and biology perspective because of a concern that either phenotypic or low MWT drug discovery might bias towards promiscuous compounds that combine on-target and off-target effects. Among ideal drug repositioning candidates (late-stage pre-clinical or clinically-experience compounds), pleiotropic activity (multiple therapeutic actions) is far more likely due to on-target effects arising where a single target mediates multiple therapeutic benefits, a desirable outcome for drug development purposes compared to the off-target alternative. Our exemplar of a low MWT compound, MLR-1023, discovered by phenotypic screening and subsequently found to have a single mechanism of action would have been overlooked based on current era medicinal chemistry precedent. The diverse therapeutic activities described for this compound by us, and others arise from the same pleiotropic lyn kinase activation molecular target. MLR-1023 serves as a proof-of-principle that potent, on target, low MWT drugs can be discovered by phenotypic screening.
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