Small Molecule Modulators of Protein-Protein Interactions: Selected Case Studies Madhu Aeluri, † Srinivas Chamakuri, † Bhanudas Dasari, † Shiva Krishna Reddy Guduru, † Ravikumar Jimmidi, † Srinivas Jogula, † and Prabhat Arya* Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus Gachibowli, Hyderabad 500046, India CONTENTS 1.. Introduction 4641 1.1. Going in for Protein-Protein Interactions and Pathways 4641 1.2. Protein-Protein Interactions and Small Mol- ecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53-MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein-Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein-Protein Interactions Cen- tered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1. Overview of Functions of IAPs 4666 5.2. Death Receptor Pathway of Caspase Activa- tion 4667 5.3. Mitochondrial Pathway of Caspase Activation 4667 5.4. Converging Points and Cross-Talk 4667 5.5. Nonpeptidic Small Molecules 4668 5.5.1. TWX Molecules: First Reported Non- peptide Inhibitor of XIAP (BIR2 domain) 4668 5.5.2. Polyphenylureas: Another Class of Non- peptide Inhibitors of XIAP (BIR2 domain) 4668 5.6. Monovalent SMAC Mimetics 4668 5.6.1. Conformationally Constrained Monova- lent SMAC Mimetics 4668 5.6.2. Isostere Design Using [7,5]-Bicyclic Scaffold 4669 5.6.3. Design and Synthesis of Azabicyclooc- tane Scaffold-Based SMAC Mimetics 4670 5.6.4. Some More Monovalent SMAC Mimetics 4670 5.6.5. Diazabicyclic Scaffold-Based Peptide Mimetics 4670 5.7. Bivalent SMAC Mimetics: Design and Syn- thesis 4671 5.7.1. Unexpected Discovery of First Bivalent SMAC Mimetic 4671 5.7.2. Bivalent Small Molecules Based on Monovalent SMAC Mimetics 4671 6. Case Study 5: Bcl-2 Protein Family and Synthetic Small Molecules 4672 6.1. BCL-2 Protein: Mitochondrial Permeabiliza- tion in Apoptosis 4674 6.2. Peptides and Peptidomimetics 4675 6.3. SAHBA 4675 6.4. Terphenyl (α-Helix Mimicry) 4675 6.5. Natural Products and their Derivatives 4676 6.5.1. Antimycin A3 4676 6.5.2. Chelerythrine 4676 6.5.3. Polyphenolic Compounds 4676 6.6. Synthetic Molecules 4678 6.6.1. HA14-1 4678 6.6.2. BH3Is 4678 6.6.3. YC137 4678 6.6.4. ABT-737 4679 6.7. Bax Activators 4679 6.8. BAX Inhibitors 4679 7. Case Study 6: Small Molecule Modulators of 14-3- 3 PPI 4681 7.1. Stabilizers of 14-3-3 PPI 4681 7.1.1. Fusicoccin A 4681 7.1.2. Pyrrolidone and Epibestatin 4683 7.2. Inhibitors of 14-3-3 PPI 4684 7.2.1. Fobisin 101 4684 7.2.2. Molecular Tweezers 4685 8. Concluding Remarks and Future Outlook 4685 Author Information 4686 Corresponding Author 4686 Special Issue: Chemical Biology of Protein-Protein Interactions Received: July 25, 2013 Published: March 27, 2014 Review pubs.acs.org/CR © 2014 American Chemical Society 4640 dx.doi.org/10.1021/cr4004049 | Chem. Rev. 2014, 114, 4640-4694