Thibault Alle, Ph. D.
Assistant Adjunct Professor
Skaggs School of Pharmacy and Pharmaceutical Sciences
Our laboratory specializes in the rational design and optimization of small-molecule therapeutics targeting microtubule dynamics, with a primary focus on tauopathies (e.g., Alzheimer’s disease), parasitic diseases (including human African trypanosomiasis and schistosomiasis), and oncology (brain and peripheral cancers). A hallmark of our microtubule-binding programs is the development of brain-penetrant molecules, achieved through structure-guided design, physicochemical optimization, and rigorous blood-brain barrier modeling.
In parallel, we advance multiple drug discovery pipelines, including:
- Novel small molecules for metabolic dysfunction-associated steatohepatitis (MASH), targeting key pathways in liver inflammation, fibrosis, and lipid metabolism.
- Targeted therapies for diverse cancers.
A core expertise of the lab lies in the systematic development and characterization of bioisosteres. We employ advanced synthetic chemistry and ADME profiling to replace metabolically labile or suboptimal functional groups, thereby enhancing potency, selectivity, pharmacokinetic properties, and intellectual property positioning across all programs.
Education:
A.A.S Chemistry (2008) Universite Montpellier 2 (France), B.S. Chemistry (2009) Universite Montpellier 2 (France), M.S. Organic chemistry (2012) Universite Lyon 1 (France), Ph.D. Organic chemistry (2015) Universite de Rouen Normandie (France), Postdoc ESPCI Paris (Prof. Janine Cossy), Postdoc UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences (Prof. Carlo Ballatore)
Pharmaceutical Chemistry I – Physicochemical properties and hit to lead development (SPPS 221)
- Conducted SAR-driven lead optimization of 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) using matched molecular pair (MMP) analyses and cellular phenotypic classification, resulting in the identification and advancement of CNDR-51997—a brain-penetrant, orally bioavailable microtubule-stabilizer that significantly reduces Aβ plaques in 5XFAD mice and tau pathology, axonal dystrophy, and gliosis in PS19 mice—now progressing through IND-enabling studies as a candidate therapeutic for Alzheimer’s disease and tauopathies.
- Designed and evaluated deuterated cystamine derivatives (d₂- and d₄-cystamine) in a CDAA-HFD model of fibrosing MASH, showing dose-dependent reductions in liver fibrosis, inflammation, and oxidative stress—with d₄-cystamine exhibiting superior efficacy—positioning isotopically reinforced aminothiols as multitargeted MASH therapeutics.
- Developed MMP analyses to quantify structure-property relationships (SPR) of fluorinated alcohols and phenols as carboxylic acid bioisosteres, enabling predictive tuning of pKa, logD7.4, and PAMPA permeability for improved drug design in brain-penetrant programs.
(1) Alle, T.et al. Structure-Property Relationships of Fluorinated Carboxylic Acid Bioisosteres. Bioorg. Med. Chem. Lett. 2023, 91, 129363. https://doi.org/10.1016/j.bmcl.2023.129363.
(2) Alle et al. Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a] Pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights. J Med Chem 2023, 66, 435–459.
(3) Yao, Y. et al. A Small‐molecule Microtubule‐stabilizing Agent Safely Reduces Aβ Plaque and Tau Pathology in Transgenic Mouse Models of Alzheimer’s Disease. Alzheimers Dement. 2024, 20 (7), 4540–4558. https://doi.org/10.1002/alz.13875.
(4) Leszczynska, A. et al. A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis. ACS Pharmacol. Transl. Sci. 2025, acsptsci.4c00738. https://doi.org/10.1021/acsptsci.4c00738.
(5) Monti, L. et al. Structure‐Activity Relationships, Tolerability and Efficacy of Microtubule‐Active 1,2,4‐Triazolo[1,5‐ a] Pyrimidines as Potential Candidates to Treat Human Afrian Trypanosomiasis**. ChemMedChem 2023, 18 (20), e202300193. https://doi.org/10.1002/cmdc.202300193.
- CNS Drug Design: Leveraging structure-guided design and matched molecular pair (MMP) analyses, we offer collaborative development of CNS-active compounds (e.g., microtubule stabilizers, tau modulators) with optimized BBB penetration and favorable CNS MPO scores.
- ADME-Guided Optimization: We provide integrated medicinal chemistry and parallel property assessment (pKa, logD₇.₄, PAMPA, solubility) to rapidly optimize hits into leads with drug-like profiles, enabling precise tuning of permeability and metabolic liability.
- Chemical Probe Synthesis (e.g., photoaffinity labeling (PAL), pull-down analogs): We design and synthesize custom chemical probes with photoreactive groups (e.g., diazirine) and affinity tags (e.g., biotin, alkyne) for target deconvolution—extending our expertise in complex heterocycle synthesis and bioisosteric replacement to enable proteome-wide identification of novel drug-target interactions.