Inicio | Investigación e innovación | Programas Científicos | Programa de Terapias Experimentales | Sección de Biología
Investigadores Científicos
- Pablo Aparicio
- Marta San Martín
Técnicos de Laboratorio
- Mª Isabel Albarrán
- Antonio Cebriá
- Claudia Díaz
- Elena Gómez-Casero
A high-quality small-molecule probe for target validation has to be cell permeable and demonstrate target engagement and selectivity, as well as pharmacological and phenotypic response. PROTACs (PROteolysis TArgeting Chimeras) have emerged as new promising pharmacological modalities. Moreover, PROTACs represent the chemical equivalent of small interfering RNA (siRNA), albeit allowing removal of a protein at a post-translational level. Parameters such as the maximum level of target degradation (Dmax), confirmation of a proteasome dependent degradation mechanism, and kinetic parameters of POI degradation and selective degradation have to be taken into account to use PROTACs for target validation. In collaboration with Marcos Malumbres, we started an early drug discovery project to develop MASTL inhibitors and PROTACs, as non-advanced inhibitors have already been described. We have been able to develop both types of molecules, generating a set of PROTACS that meet the requirements to be used as chemical tools for target validation and to define their clinical niche.
Publicaciones
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- González-Muñoz T, Di Giannatale A, García-Silva S, Santos V, Sánchez-Redondo S, Savini C, Graña-Castro O, Blanco-Aparicio C, Fischer S, De Wever O, Creus-Bachiller E, Ortega-Bertran S, Pisapia DJ, Rodríguez-Peralto JL, Fernández-Rodríguez J, Pérez-Portabella CR, Alaggio R, Benassi MS, Pazzaglia L, Scotlandi K, Ratner N, Yohay K, Theuer CP, Peinado H. (2023). Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis. Clin Cancer Res 29, 3744-3758. Publicación CNIO.
- Jimenez L, Amenabar C, Mayoral-Varo V, Mackenzie TA, Ramos MC, Silva A, Calissi G, Grenho I, Blanco-Aparicio C, Pastor J, Megías D, Ferreira BI, Link W (2022). mTORC2 Is the Major Second Layer Kinase Negatively Regulating FOXO3 Activity. Molecules 27, 5414. Publicación CNIO.
Open Access - Álvarez RM, García AB, Riesco-Fagundo C, Martín JI, Varela C, Rodríguez Hergueta A, González Cantalapiedra E, Oyarzabal J, Di Geronimo B, Lorenzo M, Albarrán MI, Cebriá A, Cebrián D, Martínez-González S, Blanco-Aparicio C, Pastor J (2021). Omipalisib inspired macrocycles as dual PI3K/mTOR inhibitors.. Eur J Med Chem 211, 113109. Publicación CNIO.
- Jimenez L, Silva A, Calissi G, Grenho I, Monteiro R, Mayoral-Varo V, Blanco-Aparicio C, Pastor J, Bustos V, Bracher F, Megías D, Ferreira BI, Link W (2021). Screening health-promoting compounds for their capacity to induce the activity of FOXO3. J Gerontol A-Biol (in press). Publicación CNIO.
- Moore G, Lightner C, Elbai S, Brady L, Nicholson S, Ryan R, O'Sullivan KE, O'Byrne KJ, Blanco-Aparicio C, Cuffe S, O'Neill M, Heavey S, Finn SP, Gately K (2021). Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.. Cancers 13, 2139. Publicación CNIO.
- Martínez-González S, Alvarez RM, Martín JI, García AB, Riesco-Fagundo C, Varela C, Rodríguez Hergueta A, González Cantalapiedra E, Albarrán MI, Gómez-Casero E, Cebriá A, Aguirre A, Ajenjo N, Cebrián D, Geronimo B, Cunningham D, O'Neill M, Dave HPG, Blanco-Aparicio C, Pastor J (2021). Macrocyclization as a source of desired polypharmacology. Discovery of triple PI3K/mTOR/PIM inhibitors.. ACS Med Chem Lett 12, 1794-1801. Publicación CNIO.
- Lynch CJ, Bernad R, Martínez-Val A, Shahbazi MN, Nóbrega-Pereira S, Calvo I, Blanco-Aparicio C, Tarantino C, Garreta E, Richart-Ginés L, Alcazar N, Graña-Castro O, Gómez-Lopez G, Aksoy I, Muñoz-Martín M, Martinez S, Ortega S, Prieto S, Simboeck E, Camasses A, Stephan-Otto Attolini C, Fernandez AF, Sierra MI, Fraga MF, Pastor J, Fisher D, Montserrat N, Savatier P, Muñoz J, Zernicka-Goetz M, Serrano M (2020). Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases. Nat Cell Biol 22, 1223-1238. Publicación CNIO.
- Ferrara-Romeo I, Martinez P, Saraswati S, Whittemore K, Graña-Castro O, Thelma Poluha L, Serrano R, Hernandez-Encinas E, Blanco-Aparicio C, Maria Flores J, Blasco MA (2020). The mTOR pathway is necessary for survival of mice with short telomeres.. Nat Commun 11, 1168. Publicación CNIO. Open Access
- Mohlin S, Hansson K, Radke K, Martinez S, Blanco-Apiricio C, Garcia-Ruiz C, Welinder C, Esfandyari J, O'Neill M, Pastor J, von Stedingk K, Bexell D (2020). Anti?tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL?302 in neuroblastoma. EMBO Mol Med 12, e11749. Publicación CNIO.
- Esteban-Burgos L, Wang H, Nieto P, Zheng J, Blanco-Aparicio C, Varela C, Gómez-López G, Fernández-García F, Sanclemente M, Guerra C, Drosten M, Galán J, Caleiras E, Martínez-Torrecuadrada J, Fajas L, Peng SB, Santamaría D, Musteanu M, Barbacid M (2020). Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas. Proc Natl Acad Sci USA 117, 24415-24426. Publicación CNIO.
- Kennedy SP, O'Neill M, Cunningham D, Morris PG, Toomey S, Blanco-Aparicio C, Martinez S, Pastor J, Eustace AJ, Hennessy BT (2020). Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer.. Oncogene 39, 3028-3040. Publicación CNIO.
- Cash TP, Alcalá S, Rico-Ferreira MDR, Hernández-Encinas E, García J, Albarrán MI, Valle S, Muñoz J, Martínez-González S, Blanco-Aparicio C, Pastor J, Serrano M, Sainz B Jr (2020). Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells. Cancers 12, 1790. Publicación CNIO. Open Access
- Martínez-González S, García AB, Albarrán MI, Cebriá A, Amezquita-Alves A, García-Campos FJ, Martínez-Gago J, Martínez-Torrecuadrada J, Muñoz IG, Blanco-Aparicio C, Pastor J (2020). Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.. Eur J Med Chem 201, 112443. Publicación CNIO.
- Klett J, Gómez-Casero E, Méndez-Pertuz M, Urbano-Cuadrado M, Megias D, Blasco MA, Martínez S, Pastor J, Blanco-Aparicio C (2020). Screening protocol for the identification of modulators by immunofluorescent cell-based assay. Chem Biol Drug Des 95, 66-78. Publicación CNIO.
- Trigg RM, Lee LC, Prokoph N, Jahangiri L, Reynolds CP, Amos Burke GA, Probst NA, Han M, Matthews JD, Kai Lim H, Manners E, Martinez S, Pastor J, Blanco-Aparicio C, Merkel O, de Los Fayos Alonso IG, Kodajova P, Tangermann S, Högler S, Luo J, Kenner L, Turner SD. (2019). The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.. Nat Commun 10, 5428. Publicación CNIO. Open Access
- Bejarano L, Bosso G, Louzame J, Serrano R, Gómez-Casero E, Martínez-Torrecuadrada J, Martínez S, Blanco-Aparicio C, Pastor J, Blasco MA (2019). Multiple cancer pathways regulate telomere protection.. EMBO Mol Med 11, e10292. Publicación CNIO. Open Access
- Mohlin S, Hansson K, Radke K, Martinez S, Blanco-Aparicio C, Garcia-Ruiz C, Welinder C, Esfandyari J, O'Neill M, Pastor J, von Stedingk K, Bexell D (2019). Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.. EMBO Mol Med 11, e10058. Publicación CNIO. Open Access
- Llanos S, Megias D, Blanco-Aparicio C, Hernández-Encinas E, Rovira M, Pietrocola F, Serrano M (2019). Lysosomal trapping of palbociclib and its functional implications. Oncogene 38, 3886-3902. Publicación CNIO.
- Martínez-González S, Rodríguez-Arístegui S, Gómez de la Oliva CA, Hernández AI, González Cantalapiedra E, Varela C, García AB, Rabal O, Oyarzabal J, Bischoff JR, Klett J, Albarrán MI, Cebriá A, Ajenjo N, García-Serelde B, Gómez-Casero E, Cuadrado-Urbano M, Cebrián D, Blanco-Aparicio C, Pastor J (2019). Discovery of novel triazolo[4,3-b]pyridazin-3-yl-quinoline derivatives as PIM inhibitors. Eur J Med Chem 168, 87-109. Publicación CNIO.
- Godoy CA, Klett J, Di Geronimo B, Hermoso JA, Guisán JM, Carrasco-López C (2019). Disulfide Engineered Lipase to Enhance the Catalytic Activity: A Structure-Based Approach on BTL2.. Int J Mol Sci 20, E5245. Publicación CNIO. Open Access
