Ana-Isabel Hernández

Publications (5)12.72 Total impact

• Article: Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR.

  Sonia Martínez González, Ana Isabel Hernández, Carmen Varela, Milagros Lorenzo, Francisco Ramos-Lima, Elena Cendón, David Cebrián, Enara Aguirre, Elena Gomez-Casero, M I Albarrán, [......], Obdulia Rabal, Francisca Mulero, Teresa Gonzalez-Granda, Wolfgang Link, Jesús Fominaya, Mariano Barbacid, James R Bischoff, Pilar Pizcueta, Carmen Blanco-Aparicio, Joaquín Pastor
  [show abstract] [hide abstract]
  ABSTRACT: Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474).
  Bioorganic & medicinal chemistry letters 07/2012; 22(16):5208-14. · 2.65 Impact Factor
• Article: Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor.

  Sonia Martínez González, Ana Isabel Hernández, Carmen Varela, Sonsoles Rodríguez-Arístegui, Milagros Lorenzo, Antonio Rodríguez, Virginia Rivero, José Ignacio Martín, Carl Gustav Saluste, Francisco Ramos-Lima, [......], Julen Oyarzabal, Obdulia Rabal, Francisca Mulero, Teresa Gonzalez-Granda, Wolfgang Link, Jesús Fominaya, Mariano Barbacid, James R Bischoff, Pilar Pizcueta, Joaquín Pastor
  [show abstract] [hide abstract]
  ABSTRACT: Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
  Bioorganic & medicinal chemistry letters 03/2012; 22(10):3460-6. · 2.65 Impact Factor
• Article: Imidazo[1,2-a]pyrazines as novel PI3K inhibitors.

  Sonia Martínez González, Ana Isabel Hernández, Carmen Varela, Sonsoles Rodríguez-Arístegui, Rosa María Alvarez, Ana Belén García, Milagros Lorenzo, Virginia Rivero, Julen Oyarzabal, Obdulia Rabal, James R Bischoff, Maribel Albarrán, Antonio Cebriá, Patricia Alfonso, Wolfgang Link, Jesús Fominaya, Joaquín Pastor
  [show abstract] [hide abstract]
  ABSTRACT: Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of its signaling pathway in a wide variety of human cancers. We describe herein a novel series of imidazo[1,2-a]pyrazines as PI3K inhibitors.
  Bioorganic & medicinal chemistry letters 03/2012; 22(5):1874-8. · 2.65 Impact Factor
• Source

  Available from: Antonio Salgado

  Patent: tricyclic compounds for use as kinase inhibitors

  Joaquín Pastor, Francisco Ramos, Ana Isabel Hernández, Sonia Martínez, José Ignacio Martín, Carl-Gustave Pierre Saluste, Esther González, Carmen Blanco, Antonio Rodríguez, Ana María García Collazo, Antonio Salgado, Beatriz Noya
  Ref. No: WO 2011/080510 A8, Year: 07/2011
• Source

  Available from: Oliver Renner

  Article: Chemical Interrogation of FOXO3a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases

  Wolfgang Link, Julen Oyarzabal, Beatriz G. Serelde, Maria Isabel Albarran, Obdulia Rabal, Antonio Cebriá, Patricia Alfonso, Jesus Fominaya, Oliver Renner, Sandra Peregrina, David Soilán, Plácido A. Ceballos, Ana-Isabel Hernández, Milagros Lorenzo, Paolo Pevarello, Teresa G. Granda, Guido Kurz, Amancio Carnero, James R. Bischoff
  [show abstract] [hide abstract]
  ABSTRACT: Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kα. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.
  Journal of Biological Chemistry 10/2009; 284(41):28392-28400. · 4.77 Impact Factor