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Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs
Ruth Nussinov1, Mingzhen Zhang2, Ryan Maloney2
1Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
Here, we discuss the principles of allosteric activating mutations, propagation downstream of the signals that they prompt, and allosteric drugs, with examples from the Ras signaling network. We focus on Abl kinase where mutations shift the landscape toward the active, imatinib binding-incompetent conformation, likely resulting in the high affinity ATP outcompeting drug binding. Recent pharmacological innovation extends to allosteric inhibitor (GNF-5)-linked PROTAC, targeting Bcr-Abl1 myristoylation site, and broadly, allosteric heterobifunctional degraders that destroy targets, rather than inhibiting them. Designed chemical linkers in bifunctional degraders can connect the allosteric ligand that binds the target protein and the E3 ubiquitin ligase warhead anchor. The physical properties and favored conformational state of the engineered linker can precisely coordinate the distance and orientation between the target and the recruited E3. Allosteric PROTACs, noncompetitive molecular glues, and bitopic ligands, with covalent links of allosteric ligands and orthosteric warheads, increase the effective local concentration of productively oriented and placed ligands. Through covalent chemical or peptide linkers, allosteric drugs can collaborate with competitive drugs, degrader anchors, or other molecules of choice, driving innovative drug discovery.
Insights
Allosteric drugs offer innovative therapeutic strategies by targeting protein conformations. Novel approaches like Proteolysis Targeting Chimeras (PROTACs) leverage these principles to degrade disease-causing proteins, advancing drug discovery.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Allosteric activating mutations alter protein function by changing downstream signaling.
- The Ras signaling network provides a model for understanding allosteric mechanisms.
- Abl kinase mutations can lead to drug-resistant conformations, impacting therapeutic efficacy.
Purpose of the Study:
- To discuss the principles of allosteric activating mutations and their downstream effects.
- To explore the development and application of allosteric drugs, including novel degraders.
- To highlight examples from the Ras signaling network and Abl kinase.
Main Methods:
- Analysis of allosteric activating mutations and signal propagation.
- Review of allosteric drug design, including PROTACs and heterobifunctional degraders.
- Examination of engineered linkers for precise target-E3 ligase orientation.
Main Results:
- Mutations in Abl kinase favor active conformations that resist imatinib binding.
- Allosteric inhibitors linked to PROTACs target specific sites like the Bcr-Abl1 myristoylation site.
- Designed linkers in bifunctional degraders enable precise control over target degradation.
Conclusions:
- Allosteric drugs, including PROTACs and molecular glues, represent a paradigm shift in drug discovery.
- These agents can degrade targets rather than merely inhibiting them, offering new therapeutic avenues.
- Covalent linkage of allosteric ligands with other molecules enhances drug efficacy and specificity.
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