The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods

Wagner, Bridget K.; Schreiber, Stuart L.

doi:10.1016/j.chembiol.2015.11.008

Cited by 101 publications

(78 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phenotypic screening is a powerful tool for discovering antiinfective and antiproliferative compounds27. Phenotypic cellular screens are efficient because they effectively multiplex many critical targets, identifying cytotoxic inhibitors of DNA replication, protein synthesis, secretion, transcription, or other cellular processes via a single, miniaturized assay.…”

Section: Discussionmentioning

confidence: 99%

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor

Goldgof

Durrant

Ottilie

et al. 2016

Sci Rep

View full text Add to dashboard Cite

The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor

Goldgof

Durrant

Ottilie

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…There are many covalent drugs, but most were discovered serendipitously (Bauer, 2015; Wagner and Schreiber, 2016). Thus, general design rules are still being written.…”

Section: Covalent Drug Discovery Gets Its ‘Second Wind’mentioning

confidence: 99%

Privileged Electrophile Sensors: A Resource for Covalent Drug Development

Long

Aye

2017

Cell Chemical Biology

172

View full text Add to dashboard Cite

Summary This Perspective delineates how redox signaling impacts activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side-chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing—that enables rapid reaction with an endogenous signaling electrophile—is a quintessential resource for development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally-relevant cysteines, we can simultaneously harness previously-untapped moonlighting roles of enzymes linked to redox sensing.

show abstract

“…If a drug candidate is identified through phenotypic screening, the subsequent verification of its target [68] and MOA [69] is required for the early prediction of its pharmacological and toxic effects on animal model systems. In general, drugs fail at the clinical stage for two main reasons: the lack of efficacy and/or safety issues [70].…”

Section: Pharmacological Studies Using Ips Cellsmentioning

confidence: 99%

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Hashimoto

Czysz

2016

Cells

View full text Add to dashboard Cite

Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers.

show abstract

The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action Methods

Cited by 101 publications

References 32 publications

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor

Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor

Privileged Electrophile Sensors: A Resource for Covalent Drug Development

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Contact Info

Product

Resources

About