2. Academic Validation
  3. Optimization of a Series of RIPK2 PROTACs

Optimization of a Series of RIPK2 PROTACs

  • J Med Chem. 2021 Sep 9;64(17):12978-13003. doi: 10.1021/acs.jmedchem.1c01118.
Afjal H Miah 1,  Ian E D Smith 1,  Mark Rackham 1,  Alina Mares 1,  Aditya R Thawani 1,  Rakesh Nagilla 2,  Pamela A Haile 3,  Bartholomew J Votta 4,  Laurie J Gordon 1,  Gillian Watt 1,  Jane Denyer 1,  Don T Fisher 5,  Phoebe Dace 1,  Paul Giffen 1,  Andrea Goncalves 1,  Ian Churcher 1,  Paul Scott-Stevens 6,  John D Harling 1
Affiliations

Affiliations

  • 1 Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 3 Innate Immunity Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 4 Clinical Biomarkers, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 5 Drug Design and Selection, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 6 Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
PMID: 34432979 DOI: 10.1021/acs.jmedchem.1c01118
Abstract

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of Apoptosis (IAP) family of E3 Ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

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