2. Academic Validation
  3. Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile

Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile

  • Eur J Med Chem. 2021 Dec 15:226:113895. doi: 10.1016/j.ejmech.2021.113895.
Simona Sestito 1,  Andrea Bacci 1,  Sara Chiarugi 2,  Massimiliano Runfola 1,  Francesca Gado 1,  Eleonora Margheritis 3,  Sheraz Gul 4,  Maria E Riveiro 5,  Ramiro Vazquez 6,  Samuel Huguet 7,  Clementina Manera 1,  Keyvan Rezai 7,  Gianpiero Garau 8,  Simona Rapposelli 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy.
  • 2 BioStructures Lab, IIT@NEST - Istituto Italiano di Tecnologia, 56127, Pisa, Italy; NEST, Scuola Normale Superiore, Piazza San Silvestro 12, 56127, Pisa, Italy.
  • 3 BioStructures Lab, IIT@NEST - Istituto Italiano di Tecnologia, 56127, Pisa, Italy.
  • 4 Fraunhofer Institute for Translational Medicine and Pharmacology, 22525, Hamburg, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hamburg Site, 22525, Hamburg, Germany.
  • 5 Early Drug Development Group, Boulogne-Billancourt, France. Electronic address: eugenia.riveiro@e2dg.com.
  • 6 Early Drug Development Group, Boulogne-Billancourt, France.
  • 7 Radio-Pharmacology Department, Curie Institut-René Huguenin Hospital, Saint Cloud, France.
  • 8 BioStructures Lab, IIT@NEST - Istituto Italiano di Tecnologia, 56127, Pisa, Italy. Electronic address: gianpiero.garau@iit.it.
  • 9 Department of Pharmacy, University of Pisa, 56126, Pisa, Italy; CISUP, Centre for Instrumentation Sharing Pisa University, Lungarno Pacinotti 43, 56126, Pisa, Italy. Electronic address: simona.rapposelli@unipi.it.
PMID: 34624821 DOI: 10.1016/j.ejmech.2021.113895
Abstract

We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid Cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.

Keywords

Aurora A; Dual inhibitors; Ewing sarcoma; Kinases; Multitarget compounds; PDK1.

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