Erhan KELEŞ

Araştırma

Our research focuses on uncovering the molecular underpinnings of cancer biology and advancing precision therapeutics through integrative strategies combining oncology, chemical biology, and rational drug design. Our primary mission is to develop and characterize highly selective, potent, and metabolically stable small-molecule inhibitors targeting oncogenic signaling pathways.

Our previous work has pioneered covalent inhibitor design strategies to selectively and irreversibly target phosphoinositide 3-kinase alpha (PI3Kα), offering improved isoform specificity and reduced systemic toxicity. By employing innovative techniques such as active volume scanning, structure-guided drug design, and proteome-wide chemical profiling, we have developed novel covalent probes that allow for sustained inhibition of cancer-driving PI3Kα while sparing other isoforms critical for metabolic homeostasis. These efforts are underscored by our recent patent and publications in leading journals including JACS, Chemical Science, and Journal of Medicinal Chemistry.

In parallel, we have developed new therapeutic modalities through the development of mTOR- selective inhibitors (e.g., PQR626) that are brain-penetrant and suitable for treating neurological manifestations of diseases such as tuberous sclerosis complex (TSC), circumventing the metabolic liabilities often associated with pan-PI3K inhibition.

Most recently, supported by a TÜBİTAK 2232 Fellowship, we have launched an AI-assisted platform for rational drug discovery, leveraging synergies between empirical and computational methods for discovery of next-generation cancer therapeutics. By bridging oncology, chemical biology, and computational drug discovery, our research aims to translate molecular insights into actionable strategies for precision medicine.

We are always interested in curious and hard-working masters, PhD, and postdoc candidates. Candidates are encouraged to contact Dr. Keles at erhan.keles@bogazici.edu.tr.

Seçilmiş Yayınlar

• Keles, E.*; Bissegger L.*; Constantin, T.A.*; Raguz, L.; L.; Barlow-Busch, I.; Orbegozo, C.; Schaefer, T.; Sriramaratnam, R.; Schaefer, A.; Gstaiger, M.; Burke, J.E.; Borsari, C.*, Wymann, M.P*. Rapid, Potent, and Persistent Covalent Chemical Probes to Deconvolute PI3Kα Signaling. Chemical Science, https://doi.org/10.1039/D4SC05459H (2024) (*Joint 1st authors).
   
• Keles, E.*; Borsari, C.*; McPhail, J.A.; Schaefer, A.; Sriramaratnam, R.; Schaefer, T.; Gstaiger, M.; Burke, J.E.; Wymann, M.P. Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα. J. Am. Chem. Soc. 144, 6326−6342 (2022). (*Joint 1st authors) https://doi.org/10.1021/jacs.1c13568
   
• Keles, E.*; Borsari, C.*; Treyer, A.; De Pascale, M.; Hebeisen, P.; Hamburger, M.; Wymann, M.P. Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood-brain barrier permeability. RSC Med. Chem., 12, 579–583 (2021) (* Joint 1st authors). https://doi.org/10.1039/D0MD00408A
   
• Borsari, C.; Keles, E.; Rageot, D.; Treyer, A.; Bohnacker, T.; Bissegger, L.; De Pascale, M.; Melone, A.; Sriramaratnam, R.; Beaufils, F.; Hamburger, M.; Hebeisen, P.; Löscher, W.; Fabbro, D.; Hillman, P.; Wymann, M.P. 4‐(Difluoromethyl)-5-(4-((3R,5S)‐ 3,5dimethylmorpholino)-6-((R)‐3- methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders. J. Med. Chem. 63, 13595-13617 (2020). https://dx.doi.org/10.1021/acs.jmedchem.0c00620
   
• Rageot, D.; Bohnacker, T.; Keles, E.; McPhail, J.A.; Hoffmann, R.M.; Melone, A.; Borsari, C.; Sriramaratnam, R.; Sele, A.M.; Beaufils, F.; Hebeisen, P.; Fabbro, D.; Hillman, P.; Burke, J.E.; Wymann, M.P. (S)‐4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5- triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase. J. Med. Chem. 62, 13, 6241-6261 (2019). https://doi.org/10.1021/acs.jmedchem.9b00525
   
• Borsari, C.; Rageot, D.; Beaufils, F.; Bohnacker, T.; Keles, E.; Buslov, I.; Melone, A.; Sele, A.M.; Hebeisen, P.; Fabbro, D.; Hillman, P.; Wymann, M. P. Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety. ACS Med. Chem. Lett. 10, 1473-1479 (2019). https://doi.org/10.1021/acsmedchemlett.9b00333
   
• Choi, S.H.; Stuckey, D.W.; Pignatta, S.; Reinshagen, C.; Khalsa, J.K.; Roozendaal, N.; Martinez-Quintanilla, J.; Tamura, K.; Keles, E; Shah, K. Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNβ in Glioblastomas. Clin. Cancer Res. 23, 22, 7047-7058 (2017). https://doi.org/10.1158/1078- 0432.CCR-17-0077