Design and optimization strategies of PROTACs and its Application, Comparisons to other targeted protein degradation for multiple oncology therapies

• Published in: Bioorganic chemistry Vol. 154; p. 107984
• Main Authors: Malarvannan, M, Unnikrishnan, Sujith, Monohar, S, Ravichandiran, V, Paul, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2025
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; AUTOTACs; Drug Design; Humans; LYTACs; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Off-target proteins; PROTACs; Proteolysis - drug effects; Proteolysis Targeting Chimera; Ubiqutination; AUTOTACs; PROTACs; Off-target proteins; Ubiqutination; LYTACs
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107984

[Display omitted] •A comprehensive chemico-biological review on proximity pharmacology induced medicinal chemistry strategies of PROTACs.•Overview on challenges, viewpoints, and most current research results of PROTACs technology.•Discussed about the possible benefits and comparision with other targeted protein degraders (LYTACs, AUTOTACs). Recent years have witnessed notable breakthroughs in the field of biotherapeutics. Proteolysis Targeting Chimeras (PROTACs) are novel molecules which used to degrade particular proteins despite the blockage by small drug molecules, which leads to a predicted therapeutic activity. This is a unique finding, especially at the cellular level targets degradations. Clinical trials and studies on PROTACs are in progress for oncology indications for demonstration of high potency and activity. PROTAC molecules are having excellent tissue distribution properties and their capacity to mutate the proteins and target overexpressed. This concept has attained wide attention from modern researchers in oncological drug discovery with particular physical qualities not offered by other therapeutic approaches. The modular nature of the PROTACs enables their methodical optimization and logical design. A thorough review was conducted in order to delve deeper into the subject and gain a better understanding of its development, computational supports, important factors for the optimization of developed PROTAC candidates, pharmacokinetic and pharmacodynamic (PK-PD) aspects, safety risks such as the degradation of undesired proteins, and other PROTAC-related issues and their target immunotherapeutic response. Furthermore discussed about the benefits, possible challenges, viewpoints, comparison with other targeted protein degraders (LYTACs, AUTOTACs) and the most current research results of PROTACs technology in multiple oncology therapies. Abbreviations: PROTACs, Proteolysis Targeting Chimeras; PK, Pharmacokinetic; PD, Pharmacodynamic; MetAP-2, (methionine aminopeptidase 2); BCL6, B-cell lymphoma 6; GCN5, General Control Nonderepressible 5; BKT, Bruton’s tyrosine kinase; BET, Bromodomain and extra-terminal; AR, Androgen or Androgen receptor; ER, Estrogen or Estrogen receptor; FDA, Food and Drug Administration; mCRPC, Metastatic castration-resistant prostate cancer; STAT3, Signal Transducer and Activator of Transcription 3; FAK, Focal adhesion kinase; POI, Protein of interest; PEG, Polyethylene glycol; UPS, Ubiquitin-Proteasome System; VHL, Von Hippel–Lindau; CRBN, Cereblon; MDM2, Mouse Double Minute 2 homologue; cIAP, Cellular Inhibitor of Apoptosis; RNF, Ring Finger Protein; BRD, Bromodomain; CDK, Cyclin-dependent kinase; PAMPA, Parallel Artificial Membrane Permeability studies; BRET, Bioluminescence Resonance Energy Transfer; MCL, Mantle cell lymphoma; MCL-1, Myeloid Cell Leukemia 1; BCL-XL, B-cell lymphoma extra-large; TRK, Tropomyosin Receptor Kinase; RTKs, Transmembrane Receptor Tyrosine Kinase; NTRK, Neurotrophic Tyrosine Receptor Kinase; DHT, Dihydrotestosterone; EGFR, Epidermal Growth Factor Receptor; EGFR-TKIs, EGFR tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; BCR, B-cell receptor; CML, Chronic myelogenous leukemia; TKI, Tyrosine kinase inhibitors; MoA, Mechanism of action; TPD, Targetted protein degraders; LYTACs, Lysosome targeting chimeras; ASGPR, Asialoglycoprotein receptor; AUTOTACs, Autophagy-Targeting Chimeras; ATTECs, Autophagy-tethering compounds; CRISPR-Cas9, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9; TALEN, Transcription Activator-Like Effector Nuclease; ZFN, Zinc Finger Nuclease.