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

SESTITO, SIMONA; BACCI, ANDREA; CHIARUGI, SARA; RUNFOLA, MASSIMILIANO; GADO, FRANCESCA; MARGHERITIS, ELEONORA; GUL, SHERAZ; RIVEIRO, MARIA E.; VAZQUEZ, RAMIRO; HUGUET, SAMUEL; MANERA, CLEMENTINA; REZAI, KEYVAN; GARAU, GIANPIERO; RAPPOSELLI, SIMONA

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Lugar: Paris; Año: 2021

0223-5234

We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinaseinhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable forprogression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potencyagainst 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.