In this interview, we speak with Rajesh Devraj, Ph.D., President & CEO and Pol Boudes, M.D., Chief Medical Officer at Rectify Pharmaceuticals about the critical role of membrane-bound proteins, particularly ABC transporters, in disease pathophysiology. Rajesh shares insights into how Rectify Pharmaceuticals, is innovating in this space to address unmet medical needs and expand therapeutic possibilities.
Moe Alsumidaie: How do membrane-bound proteins like ABC transporters impact disease pathophysiology and clinical trials?
Rajesh Devraj: Membrane proteins, including transporters, ion channels, and GPCRs, are essential for cellular function, acting as gatekeepers for molecules entering and exiting cells. Many of these proteins have gain or loss of function mutations that drive various diseases. The pharmaceutical industry has traditionally focused on developing inhibitors or antagonists to block these proteins. However, the ability to enhance or restore protein function using small molecules is a relatively unexplored area. For instance, ABC transporters are a class of membrane proteins with 48 human variants, 21 of which have mutations causing diseases.
By targeting these transporters, we aim to mitigate biological risk by focusing on targets with strong human genetic links to disease, thus providing a more precise therapeutic approach.
Moe Alsumidaie: How is Rectify overcoming challenges in targeting ABC transporters for drug development?
Rajesh Devraj: Targeting ABC transporters has been challenging, primarily due to their structural complexity and regulatory mechanisms. However, we are building on the foundational work of companies like Vertex, which successfully targeted the CFTR gene, an ABC transporter, to treat cystic fibrosis. At Rectify, we leverage advances in cryo-EM technology, allowing us to visualize membrane proteins at high resolution, and high-throughput screening to identify small molecules that can enhance protein function rapidly. Our platform focuses on developing small molecules that directly bind to and modulate ABC transporters, enhancing their function. This involves a combination of structural biology, cellular screening, and a bespoke chemical library to find hits that increase protein expression efficiently.
Moe Alsumidaie: How do you target membrane proteins to meet unmet needs in complex diseases?
Pol Boudes: Our strategy targets membrane-bound proteins with known etiologic mutations that cause diseases. For example, our lead program targets bile acid homeostasis in the liver and biliary tract, addressing diseases like PFIC2 and PFIC3 by modulating ABCB4 and ABCB11 (also known as BSEP) transporters. These transporters are crucial for maintaining bile acid composition and regulating bile efflux, and their dysfunction leads to conditions like cholangitis and cholestasis. By developing dual-targeted positive functional modulators (PFMs), we aim to correct these dysfunctions, providing a therapeutic solution for both rare genetic and more common
diseases. The PFM approach not only addresses the genetic mutations that drives these diseases but also enhances the function of wild-type proteins, broadening the scope of potential treatments, for example to target a disease with a high unmet medical need like Primary Sclerosing Cholangitis (PSC) where there is a functional deficit of ABCB4 and ABCB11.
Moe Alsumidaie: What are the stages in developing PFMs, and how do you validate them?
Rajesh Devraj: Developing PFMs involves several critical validation stages. Initially, we conduct high-throughput screens to identify high-quality small molecule hits. These hits are then validated through the mechanism of action assays to ensure they selectively bind to the target protein rather than acting at the RNA level or as broad-spectrum chaperones. Structural biology techniques, such as cryo-EM, map the binding sites of these compounds on the target proteins. In vitro functional assays, such as primary human hepatocytes, use physiological cells to demonstrate the compounds’ efficacy. Finally, in vivo, translational disease models confirm the compounds’ therapeutic potential. These stages ensure our compounds are potent, selective, and effective in restoring protein function, and have the potential to meet the Target Product Profile (TPP) of the diseases we intend to treat.
Moe Alsumidaie: How will you expand your PFM platform to tackle other complex diseases?
Rajesh Devraj: We are expanding our PFM platform to target other complex diseases. For instance, our ABCC6 program is focused on addressing renal insufficiency and cardio-renal-metabolic diseases by targeting vascular calcification, a key driver of these conditions. Additionally, we are developing a program for a rare neurodegenerative disorder, X-linked adrenoleukodystrophy, targeting ABCD1 and D2. While I cannot provide specific timelines for these programs, our lead program is set for first-in-human studies next year. We continue to explore new targets and indications, leveraging our platform’s capabilities to develop innovative therapies for various diseases.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
