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Advancement of targeted protein degradation strategies as therapeutics for undruggable disease targets

    Mayuri P Kannan‡

    Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India

    B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India

    ‡Authors contributed equally

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    ,
    Sarojini Sreeraman‡

    Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India

    SRIIC Lab, Sri Ramachandra Institute for Higher Education & Research, Chennai, Tamil Nadu, 600116, India

    ‡Authors contributed equally

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    ,
    Chaitanya S Somala‡

    B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India

    ‡Authors contributed equally

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    ,
    Raja BS Kushwah

    B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India

    Department of Entomology and Agrilife Research, Texas A&M University, College Station, TX 77843, USA

    ,
    Saravanan K Mani

    *Author for correspondence:

    E-mail Address: saravananbioinform@bharathuniv.ac.in

    B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India

    Department of Biotechnology, Bharath Institute of Higher Education and Research, Chennai, Tamil Nadu, 600073, India

    ,
    Vickram Sundaram

    Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical & Technical Sciences (SIMATS), Thandalam, Chennai, Tamil Nadu, 602105, India

    &
    Anand Thirunavukarasou

    **Author for correspondence: Tel.: +91 999 456 2995;

    E-mail Address: anand.t@baatral.com

    B-Aatral Biosciences Private Limited, Bangalore, Karnataka, 560091, India

    SRIIC Lab, Sri Ramachandra Institute for Higher Education & Research, Chennai, Tamil Nadu, 600116, India

    Published Online:https://doi.org/10.4155/fmc-2023-0072

    Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising results in oncological, neurogenerative, cardiovascular and gynecological drug development. We provide an overview of technology advancements in TPD, including molecular glues, proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras, antibody-based PROTAC, GlueBody PROTAC, autophagy-targeting chimera, autophagosome-tethering compound, autophagy-targeting chimera and chaperone-mediated autophagy-based degraders. Here we discuss the development and evolution of the TPD field, the variety of proteins that PROTACs target and the biological repercussions of their degradation. We particularly highlight the recent improvements in TPD research that utilize autophagy or the endolysosomal pathway, which enables the targeting of undruggable targets.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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