Condensate biology: advancing drug discovery for complex diseases

Drug discovery is a complex and vital field that continually seeks to identify new therapeutic targets and develop effective treatments. In recent years, a novel approach known as condensate biology has emerged, revolutionising the way researchers think about drug discovery and development. Dewpoint Therapeutics, a platform drug discovery company founded in 2018, has been at the forefront of this exciting field. In this article, we will delve into the world of condensate biology and explore the groundbreaking research projects undertaken to discover the potential they hold for diseases such as amyotrophic lateral sclerosis (ALS) and colorectal cancer.

Dr Isaac Klein, Chief Scientific Officer at Dewpoint, brings a wealth of knowledge and expertise to the field of drug discovery. Trained as a physician scientist, he obtained his MD/PhD from Cornell Rockefeller and Sloan Kettering, specialising in Immunology, Genetics, and Cancer Biology. He now leads research and development (R&D) at Dewpoint.

Dewpoint has made significant strides in the field of drug discovery by leveraging the concept of condensates. These condensates are membrane-less microscopic structures, formed by proteins and nucleic acids and control key biological processes. Dewpoint’s breakthrough was the realisation that certain condensates are associated with human diseases. The company developed methods to identify disease-driving condensates, model them, and create systems for effective drug discovery targeting these condensates.

Klein notes the importance of Dewpoint’s disease-agnostic approach. The underlying biology and processes upon which the company was founded have broad applicability across various human disease areas. By capitalising on condensate biology, Dewpoint seeks to tackle diseases and targets that have previously lacked sufficient understanding for effective drug discovery. This approach opens up new possibilities for drug development and offers a fresh perspective on addressing previously challenging conditions like ALS, colorectal cancer and ovarian cancer. Dewpoint addresses diseases that lacked comprehensive biological understanding, allowing for more meaningful and logical drug discovery efforts. By embracing the potential of condensates, Dewpoint is pushing the boundaries of drug discovery and offering promising prospects for improving human health.

Disease research

Pushing back the boundaries of drug discovery, Klein outlines the significant progress in understanding and targeting diseases like ALS and colorectal cancer.

In the case of ALS, research in the mid to late-2010s shed light on the core biological process driving the disease, which was previously poorly understood. By modulating the condensate at the heart of ALS, Dewpoint discovered molecules that had profound physiological effects, highlighting the potential of targeting condensates in complex diseases.

Similarly, in their colorectal cancer programme, Dewpoint explored historically undruggable targets. They found that although the targets themselves may not be easily druggable due to their disordered nature, their ability to condense can be modulated using small molecules. By focusing on molecules that modulate the condensate formation, they identified tractable chemical matter that specifically impacted the target of interest. This breakthrough revealed new possibilities for hitting previously undruggable targets through innovative approaches.

The identification and feasibility assessment of potential targets rely heavily on human genetics. Dewpoint uses human genetics to nominate targets with strong disease genetics and that exhibit the characteristics of condensate formation. By combining this knowledge with a deep understanding of how proteins condense, researchers can pursue high value condensate targets driving various diseases with high unmet need.

Safety and efficacy

Regarding drug efficacy and safety evaluation, according to Klein, disease-relevant models are created of the nominated condensates. These models reflect the disease context and include relevant components and modifications observed in the disease. By studying the impact of small molecules on these disease-relevant condensates, the aim is to find molecules that effectively modulate the condensates and restore cell health.  To ensure specificity and minimise toxicity, Dewpoint has developed the condensate painting platform, which monitors the activity of small molecules against key condensates governing normal cell function.

When it comes to challenges like resistance and efficacy, Klein explains that he has not encountered significant issues with lack of efficacy so far. The disease relevance of their models and the profound impact of condensate modulation on physiological parameters contribute to the efficacy of their small molecules. However, resistance is a challenge that is just starting to be addressed as the condensate-specific molecules progress into preclinical development.

In terms of patents and regulatory aspects, Dewpoint’s approach to identifying compounds through condensate modulation and their novel mechanisms of action has allowed them to navigate the patent landscape with relative ease. As for regulatory considerations, Klein anticipates engaging in discussions with regulators to address novel aspects such as mechanism, toxicology, and dosing regimens.

Klein highlights the reliance on various technologies to advance Dewpoint’s research. The deep understanding of the biophysical and chemical parameters governing condensate formation involves employing machine learning and artificial intelligence. High-content imaging, combined with image analysis techniques, allows them to observe and analyse condensates in disease-relevant systems, enabling the selection and development of the most promising drugs.

Next steps

Looking ahead, Klein envisions a future where the fundamental biological principles of phase separation and condensate formation are widely recognised and applied. He believes that condensates regulate numerous cellular processes and are dysregulated in various diseases. With the potential to impact diverse areas of science and medicine, the aim is to establish condensate biology as a fundamental branch of cell biology – “cell biology 2.0”.