Main Area of Interest
Prostate cancer is one of the most prevalent cancers in the male population. Each year, approximately 400,000 patients are diagnosed with the disease in the seven major markets. Patients diagnosed with early-stage prostate cancer have excellent prognosis and can survive for many years after surgery through a chemotherapeutic antihormonal treatment regimen. However, prolonged use of antihormonal drugs often results in the disease becoming hormone-refractory, where prognosis deteriorates dramatically due to the lack of effective treatment. The existing antihormonal treatment for prostate cancer, androgen ablation therapy (AAT), focuses on preventing binding of the endogenous androgen receptor (AR) ligand, 5alpha-dihydrotestosterone (DHT), by competitively binding to the ligand-binding pocket (LBP) of the AR. Existing chemotherapeutics following that strategy have high dosing requirements and so exhibit significant side-effects and are prone to hormone-refraction resistance on continued administration. There is clearly an unmet medical need for new non-hormonal antiandrogens.
The development of small molecule modulators of the AR which do not target the traditional AAT route is an important field of commercially relevant research and is the overriding goal of the proposed project. This project is intended to expand the understanding of the structure-activity relationships (SAR) of these ligands and so improve selectivity, potency and affinity for the AF2 site in AR. Proof of concept will be attained on demonstration of functional utility of the most potent members in prostate cancer cell lines. Furthermore, Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET) properties and effects will be examined computationally to avoid later detrimental ADMET issues when progressing candidate compounds through the programme. The project is multidisciplinary in Medicinal Chemistry and comprises:
- Theoretical studies of interaction of the new modulators with models of androgen receptor.
- QSAR, structure-based drug design (SBDD) and ligand-based drug design (LBDD).
- Pharmacokinetical (ADMET) and Physicochemical measurements (Partition Coefficient).
- Biological evaluations (FP & FRET).
History:
- From 03/2011 Post-Doc in Molecular Design Group of the Dr. David Lloyd
- School of Biochemistry and Immunology, Trinity College Dublin (Ireland)
- 01/2010 - 12/2010 Post-Doc in the Medicinal Chemistry Group of the Dr. Isabel Rozas,
- Scool of Chemistry, Trinity College Dublin (Ireland).
- 01/2007 ~V 12/2009 Post-Doc in the Theoretical Group of the Prs. Ibon Alkorta and Jose Elguero,
- Instituto de Quemica Medica CSIC (Madrid, Spain).
- 09/2001 ~V 11/2006 Ph.D. student in the Heterocyclic Chemistry Group of the Pr. Belen Abarca,
- Departament of Organic Chemistry, University of Valencia (Valencia, Spain)
- 05/2001 ~V 09/2001 Trainee in the Heterocyclic Chemistry Group of the Pr. Belen Abarca
- Departament of Organic Chemistry, University of Valencia (Valencia, Spain)
Recent Publications
1) Chiral recognition in self-complexes of diketopiperazine derivatives
Blanco F.; Alkorta I.; Rozas, I; Elguero J.
J. Phys. Org. Chem. 23, 1155~V1172 (2010)
2) Cooperativity in multiple inusual weak bonds
Alkorta I.; ,Blanco F.; Dey P. M.; Elguero J.; Estarellas C.; Frontera A.
Theor. Chem. Account 126, 1-14 (2010)
3) 3-(Pyridin-2-yl)[1,2,3]triazolo[1,5-a]quinoline: A Theoretical and Experimental Analysis of Ring-Chain Isomerisation
Ballesteros-Garrido R.; Blanco F.; Ballesteros R.; Leroux F.; Abarca B.; Colobert F.; Alkorta I.; Elguero J.
Eur. J. Org. Chem. 5765-5778 (2009)
4) Simultaneous Interaction of Tetrafluoroethene with Anions and Hydrogen-Bond Donors: A Cooperativity Study
Alkorta, I.; Blanco, F.; Elguero, J.; Estarellas, C.; Frontera, A.; Quinonero, D.; Deya, P. M.
J. Chem. Theory Comput., 5, 1186-1194 (2009)
5) Theoretical Study of the 1:1 Complexes between Carbon Monoxide and Hypohalous Acids
Blanco, F.; Alkorta, I.; Solimannejad, M.; Elguero, J.
J. Phys. Chem. A, 113, 3237–3244 (2009)
6) A computational study of the cooperativity in clusters of interhalogen derivatives
Alkorta, I.; Blanco, F.; Elguero, J.
Struct. Chem., 20, 63-71 (2009)
7) N-sigma versus pi configuration in mono- and bis-pyrrole and imidazole derivatives of alkaline earth metals
Blanco, F.; Alkorta, I.; Elguero, J.
J. Phys. Org. Chem., 22, 747-755 (2009)
8) [1,2,3]Triazolo[1,5-a]pyridines. A theoretical (DFT) study of the ring–chain isomerization
Blanco, F.; Alkorta, I.; Elguero, J.; Cruz, V.; Abarca, B.; Ballesteros, R.
Tetrahedron, 2008, 64, 11150–11158
9) Competition of Hydrogen Bonds and Halogen Bonds in Complexes of Hypohalous Acids with Nitrogenated Bases
Alkorta, I.; Blanco, F.; Solimannejad, M.; Elguero, J.
J. Phys. Chem. A, 2008, 112, 10856–10863
10) The structure of alkali metal derivatives of azoles: N-sigma versus pi-structures
Alkorta, I.; Blanco, F.; Elguero, J.
J. Phys. Chemi. A, 2008, 112, 7682–7688
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