Siobhan Malany

Siobhan Malany, Ph.D.

Associate Professor

Department: Pharmacodynamics
Business Phone: (352) 273-6004
Business Email: smalany@cop.ufl.edu

About Siobhan Malany

Siobhan Malany received her Ph.D. in organic chemistry and enzymology at the University of Iowa and completed a postdoctoral fellowship in pharmacology at the University of California, San Diego prior to extending her studies at the Max-Planck Institute for Brain Research in Germany as an Alexander von Humboldt Fellow. Returning to San Diego, Malany led receptor pharmacology drug discovery efforts at Neurocrine Biosciences. In 2010, Malany joined the Sanford Burnham Prebys Institute in Orlando. As Director of Translational Biology, her research focused on receptor pharmacology and human stem cell-derived phenotypic platforms for therapeutic discovery for cardiometabolic diseases. She was recipient of the 2014 GSK Discovery Partnership with Academia Award. In Florida, she became interested in space medicine and is studying the effects of microgravity on human muscle biology using an automated tissue chip system as a microphysiological model of age-related musculoskeletal disease. Malany was named one of 2017 Faces of Technology by Florida’s High Tech Corridor and in 2018, her lab-on-a-chip payload launched to the ISS on Cygnus NG-10 vehicle. Shortly thereafter, she received a mayoral proclamation for her achievements in STEM.

Research Profile

Research in my laboratory seeks to implement improved in vitro cell based systems to better predict human drug efficacy particularly for age-related diseases by 1) leveraging the physiological relevance of patient-specific cells in combination with phenotypic microscopy and chemogenomic approaches to measure changes in responses to physical stressors; and 2) advance receptor target-based platforms using receptor-specific and selective ligands and mechanistic pharmacology approaches to understand drug mode of action (e.g. kinetics, allosterism).

With funding from NIH-NCATS Tissue Chip Program, we are developing a microphysiological system for age-related muscle wasting (sarcopenia). We are using patient-specific muscle primary cells in 3D culture integrated into a millifluidic device that will be placed on the International Space Station research laboratory to serve as a micro-scale model for studying physical changes induced in microgravity that may mimic aging and for predictive drug and toxicology testing to aide in the development of therapeutics for sarcopenia.

The natriuretic peptide receptors GC-A and GC-B mediate the effects of a family of hormone peptides. Elevated levels of ANP and BNP target the GC-A receptor and provide protection against hypertension and metabolic syndrome; whereas, CNP activation of the GC-B receptor provides anti-fibrotic benefit. We are focused, in collaboration with the Mayo Clinic, on the discoveryofsmallmoleculeallostericpotentiators of GC receptor / cGMP signalingpathway as therapeutics for cardiovascular disease.

The chemokine receptor, CXCR6 is a seven transmembrane domain G protein–coupled receptor (GPCR) target for the natural ligand, CXCL16, a chemokine that attracts natural killer T cells to the liver. We have developed small molecule antagonists targeting the CXCR6/CXCL16 axis to understand mechanism of action and therapeutic potential in liver fibrosis and disease.

Publications

2020
Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma.
Bioorganic & medicinal chemistry letters. 30(4) [DOI] 10.1016/j.bmcl.2019.126899. [PMID] 31882297.
2020
Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.
International journal of molecular sciences. 21(24) [DOI] 10.3390/ijms21249557. [PMID] 33334026.
2018
A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis
. 11:1-15
2018
A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis.
Disease models & mechanisms. 11(9) [DOI] 10.1242/dmm.033530. [PMID] 30254132.
2018
Discovery of Novel Small-Molecule Inducers of Heme Oxygenase-1 That Protect Human iPSC-Derived Cardiomyocytes from Oxidative Stress.
The Journal of pharmacology and experimental therapeutics. 364(1):87-96 [DOI] 10.1124/jpet.117.243717. [PMID] 29101218.
2016
Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility.
Toxicology and applied pharmacology. 305:250-258 [DOI] 10.1016/j.taap.2016.06.025. [PMID] 27343406.
2016
MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.
The Journal of clinical investigation. 126(9):3567-79 [DOI] 10.1172/JCI87382. [PMID] 27500491.
2015
Design of high-throughput screening assays and identification of a SUMO1-specific small molecule chemotype targeting the SUMO-interacting motif-binding surface.
ACS combinatorial science. 17(4):239-46 [DOI] 10.1021/co500181b. [PMID] 25719760.
2015
Discovery of ML358, a Selective Small Molecule Inhibitor of the SKN-1 Pathway Involved in Drug Detoxification and Resistance in Nematodes.
ACS chemical biology. 10(8):1871-9 [DOI] 10.1021/acschembio.5b00304. [PMID] 25946346.
2015
Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies.
Expert opinion on therapeutic targets. 19(5):589-603 [DOI] 10.1517/14728222.2015.1009448. [PMID] 25785645.
2014
Identification of Inhibitors of triacylglyceride accumulation in muscle cells: comparing HTS results from 1536-well plate-based and high-content platforms.
Journal of biomolecular screening. 19(1):77-87 [DOI] 10.1177/1087057113501198. [PMID] 23989452.
2013
An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans.
PloS one. 8(4) [DOI] 10.1371/journal.pone.0062166. [PMID] 23637990.
2012
Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia.
Bioorganic & medicinal chemistry letters. 22(1):421-6 [DOI] 10.1016/j.bmcl.2011.10.115. [PMID] 22153347.
2011
Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6.
Bioorganic & medicinal chemistry letters. 21(3):947-51 [DOI] 10.1016/j.bmcl.2010.12.053. [PMID] 21232954.
2010
Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia.
Bioorganic & medicinal chemistry letters. 20(19):5874-8 [DOI] 10.1016/j.bmcl.2010.07.117. [PMID] 20800486.
2010
Novel benzothiophene H1-antihistamines for the treatment of insomnia.
Bioorganic & medicinal chemistry letters. 20(7):2316-20 [DOI] 10.1016/j.bmcl.2010.01.134. [PMID] 20188547.
2010
Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia.
Bioorganic & medicinal chemistry letters. 20(8):2629-33 [DOI] 10.1016/j.bmcl.2010.02.055. [PMID] 20227880.
2010
The discovery and structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia.
Bioorganic & medicinal chemistry letters. 20(9):2916-9 [DOI] 10.1016/j.bmcl.2010.03.027. [PMID] 20347297.
2009
Analytical method for simultaneously measuring ex vivo drug receptor occupancy and dissociation rate: application to (R)-dimethindene occupancy of central histamine H1 receptors.
Journal of receptor and signal transduction research. 29(2):84-93 [DOI] 10.1080/10799890902721339. [PMID] 19308787.
2009
Brain-penetrating 2-aminobenzimidazole H(1)-antihistamines for the treatment of insomnia.
Bioorganic & medicinal chemistry letters. 19(15):4380-4 [DOI] 10.1016/j.bmcl.2009.05.086. [PMID] 19553115.
2009
Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia.
Journal of medicinal chemistry. 52(17):5307-10 [DOI] 10.1021/jm900933k. [PMID] 19663387.
2009
N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy.
Journal of medicinal chemistry. 52(3):709-17 [DOI] 10.1021/jm800908d. [PMID] 19140664.
2008
2,6-Diaryl-4-acylaminopyrimidines as potent and selective adenosine A(2A) antagonists with improved solubility and metabolic stability.
Bioorganic & medicinal chemistry letters. 18(20):5402-5 [DOI] 10.1016/j.bmcl.2008.09.048. [PMID] 18835161.
2008
2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.
Bioorganic & medicinal chemistry letters. 18(4):1269-73 [DOI] 10.1016/j.bmcl.2008.01.036. [PMID] 18249540.
2008
2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents.
Journal of medicinal chemistry. 51(6):1719-29 [DOI] 10.1021/jm701185v. [PMID] 18307292.
2008
2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.
Journal of medicinal chemistry. 51(6):1730-9 [DOI] 10.1021/jm701187w. [PMID] 18307293.
2008
Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.
Journal of medicinal chemistry. 51(3):400-6 [DOI] 10.1021/jm070623o. [PMID] 18189346.
2008
Lead optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinson’s disease.
Journal of medicinal chemistry. 51(22):7099-110 [DOI] 10.1021/jm800851u. [PMID] 18947224.
2008
Synthesis of N-pyrimidinyl-2-phenoxyacetamides as adenosine A2A receptor antagonists.
Bioorganic & medicinal chemistry letters. 18(6):1778-83 [DOI] 10.1016/j.bmcl.2008.02.032. [PMID] 18329269.
2006
A novel cell-based assay for G-protein-coupled receptor-mediated cyclic adenosine monophosphate response element binding protein phosphorylation.
Journal of biomolecular screening. 11(4):351-8 [PMID] 16751331.
View on: PubMed
2006
Histamine induces interleukin-6 expression in the human synovial sarcoma cell line (SW982) through the H1 receptor.
Inflammation research : official journal of the European Histamine Research Society … [et al.]. 55(9):393-8 [PMID] 17122961.
View on: PubMed
2006
Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptor.
Biochemical pharmacology. 72(2):244-55 [PMID] 16750175.
View on: PubMed
2001
Point mutations identify the glutamate binding pocket of the N-methyl-D-aspartate receptor as major site of conantokin-G inhibition.
Neuropharmacology. 41(6):753-61 [PMID] 11640930.
View on: PubMed
2000
Orientation of alpha-neurotoxin at the subunit interfaces of the nicotinic acetylcholine receptor.
Biochemistry. 39(50):15388-98 [PMID] 11112524.
View on: PubMed
2000
Pairwise electrostatic interactions between alpha-neurotoxins and gamma, delta, and epsilon subunits of the nicotinic acetylcholine receptor.
The Journal of biological chemistry. 275(8):5478-84 [PMID] 10681526.
View on: PubMed
2000
Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure.
Pflugers Archiv : European journal of physiology. 440(Suppl 1):R115-R117 [DOI] 10.1007/s004240000028. [PMID] 28008504.
1999
Subunit interface selectivity of the alpha-neurotoxins for the nicotinic acetylcholine receptor.
The Journal of biological chemistry. 274(14):9581-6 [PMID] 10092644.
View on: PubMed
1999
Theoretical and experimental investigations of electrostatic effects on acetylcholinesterase catalysis and inhibition.
Chemico-biological interactions. 119-120:99-110 [PMID] 10421443.
View on: PubMed

Grants

Sep 2020 ACTIVE
Electrical Stimulation of Human Myocytes in Microgravity: An In Vitro Model to Evaluate Therapeutics to Counteract Muscle Wasting
Role: Principal Investigator
Funding: NATL INST OF HLTH NCATS
Aug 2020 ACTIVE
Advancing small molecule CXCR4 agonists for diabetic wound healing
Role: Principal Investigator
Funding: UNIV OF COLORADO via NATL INST OF HLTH NIDDK
Jan 2019 ACTIVE
Transcriptional Gene analysis of human muscle cells grown in microgravity and preserved in a microfluidic lab-on-a-chip.
Role: Principal Investigator
Funding: MICRO-GRX via SPACE FLORIDA
Dec 2018 – Aug 2020
Electrical Stimulation of Human Myocytes in Microgravity: An In Vitro Model to Evaluate Therapeutics to Counteract Muscle Wasting
Role: Principal Investigator
Funding: NATL INST OF HLTH NCATS
Dec 2018 ACTIVE
Small Molecule Discovery for Particulate Guanylyl Cyclase Receptor B Enhancers
Role: Principal Investigator
Funding: MAYO CLINIC via NATL INST OF HLTH NIA
Dec 2018 – Nov 2019
Identifying CxCR4 Receptor Agonists to Improve Diabetic Healing
Role: Principal Investigator
Funding: UNIVERSITY OF COLORADO DENVER via NATL INST OF HLTH NIDDK

Education

Ph.D.
1997 · University of Iowa
B.A.
1992 · Augustana College

Teaching Profile

Courses Taught
2020-2021
PHA5515 Prin Med Chem-Pcol II
2021
PHA4911 Undergraduate Research in Pharmacodynamics

Contact Details

Phones:
Business:
(352) 273-6004
Emails: