Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs. Issue 17 (15th September 2022)

• Record Type: Journal Article
• Authors: Nussinov, Ruth; Zhang, Mingzhen; Maloney, Ryan; Liu, Yonglan; Tsai, Chung-Jung; Jang, Hyunbum
• Is Part Of: Journal of molecular biology. Volume 434:Issue 17(2022)
• Publication Date: 2022-09-15
• Subjects: ensembles -- allosteric PROTAC -- allosteric molecular glues -- autoinhibition -- kinase drug discovery; MD molecular dynamics -- NMR nuclear magnetic resonance -- AKT protein kinase B -- mTOR mammalian target of rapamycin -- PI3K phosphoinositide 3-kinase -- SHP2 SH2 domain-containing phosphatase 2 -- NEK NIMA-related kinase -- MARK MAP/microtubule affinity-regulating kinase -- KA1 kinase-associated-1 -- PTEN phosphatase and tensin homolog -- PIP2 phosphatidylinositol 4, 5-bisphosphate -- PIP3 phosphatidylinositol 3, 4, 5-trisphosphate -- ABD adaptor binding domain -- RTK receptor tyrosine kinase -- MAPK mitogen-activated protein kinase -- CR conserved region -- RBD Ras binding domain -- CRD cysteine rich domain -- MEK mitogen-activated protein kinase kinase -- A-loop activation loop -- PBM PIP2-binding motif -- CTT C-terminal tail -- ASD autism spectrum disorder -- GAP GTPase-activating protein -- EGFR epidermal growth factor receptor -- PDGFR platelet-derived growth factor receptor -- ALL acute lymphoblastic leukemia -- CML chronic myeloid leukemia -- CML-N neutrophilic-chronic myeloid leukemia -- TKI tyrosine kinase inhibitor -- RORγ RAR-related orphan receptor γ -- PROTAC proteolysis targeting chimera -- IMiD immunomodulatory imide drug -- CRBN cereblon -- Sig1R sigma-1 receptor -- CDK cyclin-dependent kinase -- GPCR G protein-coupled receptor; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2022.167569
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: We overview the principles of allosteric activating mutations and allosteric drugs. Examples of activating mutations include the Ras signaling network and Abl kinase. We overview innovative allosteric drug concepts, underscoring the challenge. The review links allostery on the molecular level and productive cell signaling. From the cellular standpoint, we propose a signaling by-the-numbers lens. 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.