Researchers at Weill Cornell Medicine have introduced a promising advancement in the field of cancer immunotherapy, potentially streamlining and enhancing the process of identifying small molecule drug candidates to target cancer checkpoints. This new approach leverages virtual screening to quickly analyze millions of potential compounds, aiming to find small molecules that could bind to immune checkpoints and activate the immune system to combat cancer cells. Such small molecules present an alternative to current immunotherapy options, particularly monoclonal antibodies, which are large protein-based drugs that must be administered via infusion.
Checkpoint inhibitors are a critical class of cancer therapies that target specific immune “checkpoints.” These checkpoints are molecules on immune cells that, when bound to their partner proteins, signal the immune system to stop its activity, effectively “braking” immune responses. Cancer cells often exploit these checkpoints to avoid being attacked by the immune system. Current checkpoint inhibitors, all of which are monoclonal antibodies, work by blocking these interactions, thus “releasing the brakes” and enabling immune cells—particularly T cells—to attack cancer cells. However, monoclonal antibodies have limitations. They need to be infused, often require complex dosing regimens, and, due to their large size, may struggle to effectively penetrate tumors. Small molecules, on the other hand, could be taken orally, offer more flexible dosing, and, owing to their smaller size, can potentially infiltrate tumors more effectively.
The findings, published in Science Advances on October 16, demonstrate an advanced virtual screening method capable of pinpointing small molecules that can mimic the binding properties of monoclonal antibodies. According to Moustafa Gabr, assistant professor of chemistry in radiology at Weill Cornell Medicine and senior author of the study, this research represents a notable shift in cancer immunotherapy, offering a potential alternative to monoclonal antibody treatments that could improve patient experience and expand therapeutic options.
To address the unique challenges posed by immune checkpoint proteins, which have flat and flexible surfaces that often resist binding with small molecules, the research team took inspiration from the structures of immune checkpoints bound with monoclonal antibodies. By examining these structures, the researchers created “pharmacophore” maps—3D models illustrating essential binding features between the checkpoint proteins and the monoclonal antibodies. Using computational tools, they identified key interaction sites within the protein-protein interfaces of these bound checkpoint proteins. These insights helped them calculate various properties, such as binding tightness and “druggability” scores, which gauge the potential for small molecules to bind effectively to target checkpoints.
With these pharmacophore maps and calculated properties, the team conducted virtual screenings on a large database of commercially available small molecules, aiming to identify candidates that could replicate the binding interactions seen in monoclonal antibody-bound checkpoint proteins. Potential hits were further analyzed to confirm their binding affinity—the strength of the molecule’s interaction with the checkpoint protein—and specificity, ensuring the molecule targeted the intended checkpoint without binding to unrelated proteins. The researchers also conducted cell-based tests to verify how these molecules influenced immune checkpoint activity.
From this screening, two small molecules emerged as particularly promising candidates. One, named MG-T-19, was found to inhibit TIM-3, an immune checkpoint receptor associated with T cell regulation. TIM-3, an inhibitory checkpoint, plays a role in dampening immune responses, which cancer cells can exploit to evade the immune system. Blocking TIM-3 with MG-T-19 could reinvigorate T cell responses, helping the immune system to attack tumors. Another small molecule, MG-V-53, was identified as a VISTA inhibitor. VISTA is another checkpoint that helps tumors evade immune responses, and inhibiting VISTA could make tumors more vulnerable to immune attacks.
Further in vivo testing showed that both MG-T-19 and MG-V-53 significantly reduced tumor volume in mouse models, demonstrating the compounds’ potential effectiveness. According to Gabr, these small molecules exhibited not only strong binding affinities but also showed notable antitumor activity in animal models, underscoring their promise as future therapeutic options.
The study’s first author, Somaya Abdel-Rahman, assistant professor of pharmacy in the department of medicinal chemistry at Mansoura University, Egypt, contributed extensively to the research, providing critical insights into the binding properties and potential clinical applications of these compounds.
Looking ahead, the research team plans to optimize the lead compounds for clinical application. Future studies will aim to refine the molecules’ structures to maximize their efficacy and safety. Additionally, the team hopes to explore these small molecules’ potential as part of combination therapies, where they could work alongside other drugs to enhance therapeutic outcomes. The virtual screening method developed for this study also opens up possibilities for targeting other immune checkpoints, potentially broadening the scope of available treatments for a variety of cancers.
Ultimately, this approach may contribute to expanding the repertoire of cancer therapies by providing new, effective options that are more accessible for patients, particularly those who may benefit from orally administered treatments. As Gabr noted, this method of drug discovery may not only improve patient outcomes but also spark further research and innovation in cancer immunotherapy, pushing the field toward more adaptable, patient-friendly treatments that align with the complex demands of cancer care.
Source: Cornell University