A New Approach to Challenging Targets

Small molecules for challenging targets in diseases with high unmet need

Targeting TDP-43 to treat amyotrophic lateral sclerosis (ALS)

TDP-43 is the most critical regulator of the cascade of reactions that leads to ALS

TDP-43 is a vital protein involved in a wide range of cellular activities, most notably including regulation of mRNA splicing. It is involved in many neurodegenerative diseases and is the most critical regulator of the cascade of inflammatory reactions that leads to ALS. This cascade contributes to ongoing cellular stress and eventually the death of motor neurons.

In ALS, loss of motor neurons gradually limits people’s muscle control, eventually leading to the inability to swallow and breathe. There are approximately 30,000 people living with ALS in the United States, and the average lifespan after diagnosis is two to five years. There are no approved therapies that address the cause of the disease or significantly slow its progression.

ACE-2223 is a small molecule designed to specifically target misfolded TDP43 that leads to disease pathology.

In ALS, TDP-43 accumulates as large inclusions or aggregates in the cytoplasm via a toxic hexameric intermediate. These misfolded aggregated forms lead to a loss of TDP-43 function normally carried out by monomeric and dimeric forms in the nucleus. The lack of healthy TDP-43 leads to a breakdown of mRNA function, resulting in a range of incorrect or missing proteins throughout the cell.

The complexity of misfolded TDP-43 has historically made TDP-43’s structure hard to analyze. It has also rendered difficult the design of drugs that directly target it – until our work at Acelot.

Mass removal of TDP-43 from neurons leads to cellular death, an ideal drug mechanism disrupts the disease-associated form of TDP-43, thus shifting the equilibrium back to the healthy form of TDP-43. This functional TDP-43 can then appropriately regulate mRNA splicing and correct translation of a wide range of proteins.

ACE-2223: Our solution to restore TDP-43’s healthy form and function

Data supporting ACE-2223

    • Highly blood-brain-barrier (BBB) permeable

    • Reduces pathological TDP-43

    • Rescues neuroinflammation

    • Reduces neurofilament-light chain

    • Improves survival and motor function

    • Inhibits TDP-43 aggregation

    • Dissociates preformed TDP-43 aggregates

    • Rescues mRNA mis-splicing

    • Rescues functional TDP-43

    • Increases neuronal survival

    • Improves synaptic defects

Our work begins with de novo drug design to target proteins whose complex form and behavior make them challenging targets. We integrate novel AI tools, computational chemistry and assays to design and optimize small molecule candidates against these targets to create the promise of first-in-class and best-in-class drugs for devastating diseases.

* Acelot is pursuing targets that have demonstrated potential applicability in a range of neurodegenerative diseases, including TPD-43 positive fronto-temporal dementia, Alzheimer's disease (AD), inclusion body myositis, multiple system atrophy, and dementia with Lewy bodies.

Our team is focused on rigorous science and efficient development to accelerate the delivery of first-ever treatment options. We collaborate closely with leading scientists and experts in disease biology, and our backgrounds include the deep technical, discovery and entrepreneurial experience essential for pharmaceutical development.

Team

  • Katie Planey, PhD, MBA

    Chief Executive Officer

  • Lewis Whitehead, PhD

    Vice President of Research, Computational Discovery

  • Vidhu Mathur, PhD

    Senior Director, R&D

  • Valarie Truax, PhD, MBA

    Vice President, Business Development and Corporate Strategy

  • Marcie Glicksman, PhD

    Acting Chief Scientific Officer

  • Shruti Arya, PhD

    Senior Scientist I

  • Andrew Carr, PhD

    Senior Scientist

  • Marcela Kokes, PhD

    Senior Scientist I

  • Vanessa Seawright, MS

    Research Associate

  • Devi Supriya Korumilli, MS

    Research Associate

  • Cody Aldaz, PhD

    Data Scientist

  • Kevin Burk, MS, MSci

    Data Scientist

Advisors

  • Ambuj Singh, PhD

    Founder & Board Member, Acelot; UCSB Professor, Department of Computer Science, Biomolecular Science and Engineering

  • David Bleakman, PhD

    President, Drug Discovery Psychogenics; Former CSO, Eli Lilly Neuroscience; Former CSO, Redpin Therapeutics

  • Andrew Perlman, MD, PhD

    Co-founder & Managing Director, X37; Former EVP, Tularik; Former CEO, Innate Immune; Former Director of Clinical Development, Genentech

  • Mike Kavanaugh, MD, PhD

    CSO, Cytomx; Former CSO, Five Prime Therapeutics; Former VP, Novartis Vaccines & Diagnostics

  • Steve Doberstein, PhD

    Former Chief Scientist, Nektar Therapeutics; Former Senior R&D, XOMA Royalty; Former Senior R&D, Five Prime Therapeutics; Former Senior R&D, Xencor; Former Senior R&D, Exelixis

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329 Oyster Point Blvd, 3rd Floor
South San Francisco, CA 94080