Rational Polypharmacology: Systematically Identifying and Engaging Multiple Drug Targets to Promote Axon Growth

Hassan Al-Ali, Do Hun Lee, Matt C. Danzi, Houssam Nassif, Prson Gautam, Krister Wennerberg, Bill Zuercher, David H. Drewry, Jae Lee, Vance Lemmon, John Bixby

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Mammalian central nervous system (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multitarget drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds' kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line as well as targets recently shown to mediate drug resistance.

Original languageEnglish (US)
Pages (from-to)1939-1951
Number of pages13
JournalACS Chemical Biology
Volume10
Issue number8
DOIs
StatePublished - Aug 21 2015

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Polypharmacology
Axons
Neurology
Phosphotransferases
Central Nervous System
Growth
Pharmaceutical Preparations
Neurons
Assays
Information Theory
Screening
Aptitude
Enzyme Assays
Drug Discovery
Spinal Cord Injuries
Drug Resistance
Information theory
Rodentia
Learning algorithms
Modulators

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Rational Polypharmacology : Systematically Identifying and Engaging Multiple Drug Targets to Promote Axon Growth. / Al-Ali, Hassan; Lee, Do Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae; Lemmon, Vance; Bixby, John.

In: ACS Chemical Biology, Vol. 10, No. 8, 21.08.2015, p. 1939-1951.

Research output: Contribution to journalArticle

Al-Ali, Hassan ; Lee, Do Hun ; Danzi, Matt C. ; Nassif, Houssam ; Gautam, Prson ; Wennerberg, Krister ; Zuercher, Bill ; Drewry, David H. ; Lee, Jae ; Lemmon, Vance ; Bixby, John. / Rational Polypharmacology : Systematically Identifying and Engaging Multiple Drug Targets to Promote Axon Growth. In: ACS Chemical Biology. 2015 ; Vol. 10, No. 8. pp. 1939-1951.
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