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The Evolving Druggability and Developability Space: Chemically Modified New Modalities and Emerging Small Molecules

Abstract

The druggability and developability space is rapidly evolving in the post-genomic era. In the past, Lipinski’s rule-of-five (Ro5) emerged and served as a guide for drug-like molecule design for oral delivery in the traditional druggable target space. In contrast, in this new era, a transition is occurring in drug discovery towards novel approaches to bind and modulate challenging biological targets that have led to transformative treatments for patients. Consequently, drugging novel targets using a variety of emerging molecular modalities, namely beyond the Ro5 (bRo5) small molecules (such as protein-protein interaction modulators, protein-targeted chimeras, or PROTACs), peptide/peptidomimetics, and nucleic acid-based modalities, have become a key focus in drug discovery. Herein, the emerging druggability and developability space is discussed side by side to build a general understanding of the potential development challenges of these novel modalities. An overview is provided on the evolving novel targets and molecular modalities, followed by a detailed analysis of the druggability aspects as well as the strategies used to progress drug candidate, and the trending chemistry and formulation strategies used to assess developability.

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Acknowledgments

The authors thank Carolyn A. Heusser at Novartis Institutes for BioMedical Research for carefully reviewing the manuscripts and providing helpful comments for revision. The authors also thank Sara Danforth at Novartis Institutes for BioMedical Research for her key assistance on creating the figures.

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Yang, W., Gadgil, P., Krishnamurthy, V.R. et al. The Evolving Druggability and Developability Space: Chemically Modified New Modalities and Emerging Small Molecules. AAPS J 22, 21 (2020). https://doi.org/10.1208/s12248-019-0402-2

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KEY WORDS

  • beyond rule of five
  • developability
  • druggability
  • oligonucleotides
  • peptides