2. Academic Validation
  3. Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety

Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety

  • ACS Med Chem Lett. 2015 Oct 31;6(12):1241-6. doi: 10.1021/acsmedchemlett.5b00398.
Chudi O Ndubaku 1,  James J Crawford 1,  Joy Drobnick 1,  Ignacio Aliagas 1,  David Campbell 2,  Ping Dong 3,  Laura M Dornan 1,  Sergio Duron 2,  Jennifer Epler 1,  Lewis Gazzard 1,  Christopher E Heise 1,  Klaus P Hoeflich 1,  Diana Jakubiak 1,  Hank La 1,  Wendy Lee 1,  Baiwei Lin 1,  Joseph P Lyssikatos 1,  Jasna Maksimoska 4,  Ronen Marmorstein 4,  Lesley J Murray 1,  Thomas O'Brien 1,  Angela Oh 1,  Sreemathy Ramaswamy 1,  Weiru Wang 1,  Xianrui Zhao 1,  Yu Zhong 1,  Elizabeth Blackwood 1,  Joachim Rudolph 1
Affiliations

Affiliations

  • 1 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Afraxis, Inc. , 6605 Nancy Ridge Road, Suite 224, San Diego, California 92121, United States.
  • 3 Shanghai ChemPartner , 576 Libing Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, PRC.
  • 4 Perelman School of Medicine, University of Pennsylvania , 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, United States.
PMID: 26713112 DOI: 10.1021/acsmedchemlett.5b00398
Abstract

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and Cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in Cancer and Other Diseases.

Keywords

Kinase inhibitor; hERG; oncology; pKa.

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