Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs

Ruth Nussinov, Mingzhen Zhang, Ryan Maloney, Yonglan Liu, Chung Jung Tsai, Hyunbum Jang

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Article number167569
JournalJournal of Molecular Biology
DOIs
StateAccepted/In press - 2022

Keywords

  • allosteric PROTAC
  • allosteric molecular glues
  • autoinhibition
  • ensembles
  • kinase drug discovery

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