Exploring Prolonged Drug Action: The Role of Epichaperome Agents

Discover the secret behind prolonged drug action. Epichaperome target binding by zelavespib and icapamespib defies rapid clearance, shedding light on effective disease treatment.
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Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.

Exploring Prolonged Drug Action: The Role of Epichaperome Agents

Have you ever wondered why some drugs seem to work longer and more effectively than others? The answer might lie in a fascinating cellular structure known as the epichaperome. Researchers at Memorial Sloan Kettering Cancer Center have been delving into this intricate world, and their findings could change the way we think about drug treatments.

The Power of Drug Residence Time

In the realm of drug development, one crucial factor often determines a drug's effectiveness: residence time. It's the amount of time a drug lingers at its target site. Drugs with a long residence time tend to be more efficacious in treating diseases. But understanding why and how some drugs have this extended residence time has been a challenge, especially for non-covalent agents.

Enter the Epichaperome Agents

Enter epichaperome agents like zelavespib and icapamespib. These compounds have intrigued researchers for their ability to remain bound to their target for days, even after rapid clearance from plasma, minimal presence in non-diseased tissues, and fast metabolism. It's like they've cracked the code to sustained drug action.

The Epichaperome: A Molecular Hub

So, what exactly is the epichaperome? It's a complex molecular structure composed of tightly bound chaperones, co-chaperones, and other factors. Unlike chaperones, which are ubiquitous in cells, epichaperomes are primarily found in diseased cells and tissues. They play a unique role in rewiring protein-protein interactions at a proteome-wide level.

Unraveling the Mechanism

To get to the bottom of this mystery, the researchers conducted a comprehensive study. They monitored drug concentration, target occupancy, and epichaperome assemblies in a live mouse model. What they discovered was truly enlightening.

The Trapping Effect

One key finding was the trapping effect. Initially, epichaperome agents become trapped upon binding. This mechanism leads to the disassembly of epichaperomes, all without altering the expression level of epichaperome constituents. It's a process that seems to be a major contributor to the extended on-target residence time observed with these agents in clinical settings.

Implications for Drug Development

These findings have profound implications for drug development. They provide a deeper understanding of why some drugs outperform others and offer new avenues for enhancing drug efficacy. By targeting the trapping effect and manipulating drug residence time, researchers may unlock new treatment strategies for various diseases.

Conclusion

The world of drug development is constantly evolving, and the discovery of epichaperome agents' unique mechanism adds another layer to our understanding. With more research in this area, we could see the development of highly effective drugs that revolutionize disease treatment.

Stay tuned for further developments in this exciting field. The secret behind prolonged drug action is slowly being unraveled, and it promises to change the landscape of medicine as we know it.

References

Sharma S, Joshi S, Kalidindi T, Digwal CS, Panchal P, Lee S-G, Zanzonico P, Pillarsetty N, Chiosis G. Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action. Biomedicines. 2023; 11(10):2599. https://doi.org/10.3390/biomedicines11102599

Bolaender A, Zatorska D, He H, Joshi S, Sharma S, Digwal CS, Patel HJ, Sun W, Imber BS, Ochiana SO, Patel MR, Shrestha L, Shah SK, Wang S, Karimov R, Tao H, Patel PD, Martin AR, Yan P, Panchal P, Almodovar J, Corben A, Rimner A, Ginsberg SD, Lyashchenko S, Burnazi E, Ku A, Kalidindi T, Lee SG, Grkovski M, Beattie BJ, Zanzonico P, Lewis JS, Larson S, Rodina A, Pillarsetty N, Tabar V, Dunphy MP, Taldone T, Shimizu F, Chiosis G. Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system. Nat Commun. 2021 Aug 3;12(1):4669. doi: 10.1038/s41467-021-24821-2. 

Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G, Gerecitano JF, Dunphy MPS. Paradigms for Precision Medicine in Epichaperome Cancer Therapy. Cancer Cell. 2019 Nov 11;36(5):559-573.e7. doi: 10.1016/j.ccell.2019.09.007.

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Cancer Biology
Life Sciences > Biological Sciences > Cancer Biology
Drug Development
Life Sciences > Health Sciences > Biomedical Research > Pharmacology > Pharmaceutics > Drug Development
Molecular Target Validation
Life Sciences > Health Sciences > Biomedical Research > Pharmacology > Small Molecules > Molecular Target Validation
Therapeutics
Life Sciences > Health Sciences > Clinical Medicine > Therapeutics
Pharmacology
Life Sciences > Health Sciences > Biomedical Research > Pharmacology
Small Molecules
Life Sciences > Health Sciences > Biomedical Research > Pharmacology > Small Molecules