Profile
The major focus of the Lindsley laboratory is drug discovery and
medicinal chemistry. Students in my lab will collaborate with other
members of the Pharmacology, Drug Metabolism and Clinical
Pharmacology departments to pursue small molecule hits from high
throughput screens, perform lead optimization studies to develop
structure-activity-relationships (SAR) and ultimately deliver small
molecules with acceptable properties to validate novel
targets/mechanisms in in vivo animal models of target diseases. The
molecular targets of interest are kinases, GPCRs, ion channels,
nuclear hormone receptors and protein-protein interactions, with an
emphasis on allosteric modulation as opposed to classical
agonism/antagonism. Therapeutic areas of interest span cancer,
neuroscience (schizophrenia, anxiety, pain, sleep, Parkinson's
disease) and endocrinology (diabetes, obesity). Students will be
exposed to every phase of classical drug discovery. As a member of
ther Vanderbilt Institutue of Chemical Biology, training in my
laboratory will be broad and involve organic synthesis, medicinal
chemistry, pharmacology and drug metabolism. For many programs in
the neuroscience area, students will have the opportunity to also
develop radioligands for binding assay development and PET tracers
for imaging studies.
Another focus in the group is parallel synthesis and the
development of new technologies for library synthesis. The lab has
state-of-the-art microwave synthesis technology, a mass-directed
HPLC purification platform and a large collection of monomers and
polymer-supported reagents. There are a number of projects directed
at synthesizing libraries of small molecule protein-protein
inhibitors, target family-directed libraries and other drug-like
small molecule libraries for use in high throughput screening
efforts.
The third area of interest in my group is synthetic organic
chemistry. Students will have the opportunity to work on synthetic
methodology projects as well as partial and total synthesis
projects.
Publications
The following timeline graph is generated from all co-authored publications.
- Regulation of phospholipase D activity and phosphatidic acid production after purinergic (P2Y6) receptor stimulation. Scott SA, Xiang Y, Mathews TP, Cho HP, Myers DS, Armstrong MD, Tallman KA, O'Reilly MC, Lindsley CW, Brown HA (2013) J Biol Chem 288(28): 20477-87
› Primary publication · 23723068 (PubMed) · PMC3711313 (PubMed Central) - Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Engers DW, Frist AY, Lindsley CW, Hong CC, Hopkins CR (2013) Bioorg Med Chem Lett 23(11): 3248-52
› Primary publication · 23639540 (PubMed) · PMC3677712 (PubMed Central) - Spiroaminal Model Systems of the Marineosins with Final Step Pyrrole Incorporation. Panarese JD, Konkol LC, Berry CB, Bates BS, Aldrich LN, Lindsley CW (2013) Tetrahedron Lett 54(18): 2231-2234
› Primary publication · 23606772 (PubMed) · PMC3627418 (PubMed Central) - Discovery of ML326: The first sub-micromolar, selective M5 PAM. Gentry PR, Bridges TM, Lamsal A, Vinson PN, Smith E, Chase P, Hodder PS, Engers JL, Niswender CM, Daniels JS, Conn PJ, Wood MR, Lindsley CW (2013) Bioorg Med Chem Lett 23(10): 2996-3000
› Primary publication · 23562060 (PubMed) · PMC3634896 (PubMed Central) - A General, Enantioselective Synthesis of 1-Azabicyclo[.0]alkane Ring Systems. Senter TJ, Schulte ML, Konkol LC, Wadzinski TE, Lindsley CW (2013) Tetrahedron Lett 54(13): 1645-1648
› Primary publication · 23459400 (PubMed) · PMC3580858 (PubMed Central) - Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells. O'Reilly MC, Scott SA, Brown KA, Oguin TH, Thomas PG, Daniels JS, Morrison R, Brown HA, Lindsley CW (2013) J Med Chem 56(6): 2695-9
› Primary publication · 23445448 (PubMed) · PMC3632306 (PubMed Central) - Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. Gregory KJ, Nguyen ED, Reiff SD, Squire EF, Stauffer SR, Lindsley CW, Meiler J, Conn PJ (2013) Mol Pharmacol 83(5): 991-1006
› Primary publication · 23444015 (PubMed) · PMC3629835 (PubMed Central) - Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule. Poslusney MS, Melancon BJ, Gentry PR, Sheffler DJ, Bridges TM, Utley TJ, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Wood MR (2013) Bioorg Med Chem Lett 23(6): 1860-4
› Primary publication · 23416001 (PubMed) · PMC3594472 (PubMed Central) - A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Noetzel MJ, Gregory KJ, Vinson PN, Manka JT, Stauffer SR, Lindsley CW, Niswender CM, Xiang Z, Conn PJ (2013) Mol Pharmacol 83(4): 835-47
› Primary publication · 23348500 (PubMed) · PMC3608436 (PubMed Central) - Chemical modification of the M(1) agonist VU0364572 reveals molecular switches in pharmacology and a bitopic binding mode. Digby GJ, Utley TJ, Lamsal A, Sevel C, Sheffler DJ, Lebois EP, Bridges TM, Wood MR, Niswender CM, Lindsley CW, Conn PJ (2012) ACS Chem Neurosci 3(12): 1025-36
› Primary publication · 23259038 (PubMed) · PMC3526969 (PubMed Central)