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

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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.

Author information

Authors and Affiliations

  1. Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, Massachusetts, 02451, USA

    Wenzhan Yang

  2. Analytical Development-Pharmaceutics Research, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, 02139, USA

    Prajakta Gadgil

  3. Advance Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, Massachusetts, 02451, USA

    Venkata R. Krishnamurthy

  4. Molecular Pharmaceutics, Pharmaceutical Sciences, Pfizer Global Research and Development, Cambridge, Massachusetts, 02139, USA

    Margaret Landis

  5. Pharmacology, Metabolism & Pharmacokinetics Division, ScitoVation, Durham, North Carolina, 27713, USA

    Pankajini Mallick

  6. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Inc., Princeton, New Jersey, 08543, USA

    Dipal Patel

  7. Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Phenil J. Patel

  8. Synthetics Enabling Technologies, Pre-Pivotal Drug Product, Drug Product Technologies, Amgen, Inc., Cambridge, Massachusetts, 02142, USA

    Darren L. Reid

  9. Chemical & Pharmaceutical Profiling (CPP), Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, 02139, USA

    Manuel Sanchez-Felix

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  1. Wenzhan Yang
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Correspondence to Wenzhan Yang.

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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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