at the PhD programme in Pharmaceutical and Biomolecular Sciences of the University of Turin - UniTO (Italy) we have reserved scholarships for International students. We are looking for motivated students for the upcoming academic year, starting October 1, 2018, to be involved in the project named:
Targeting leukemia myeloid differentiation using innovative human Dihydroorotate Dehydrogenase (hDHODH) inhibitors
Inside the three years Ph.D, the candidate will be involved in state-of-the-art drug design research, exposing him/herself to the design of in vivo effective preclinical candidates for acute myelogenous leukemia (AML). In the specific, he/she will asked to design and synthesize the targethDHODH inhibitors. During the three years PhD, he/she will spend his/her research at the Department of Science and Drug Technology of UniTo (tutor Marco L. Lolli) and at least 6-12 months in a second research group, selected inside the connection we have with European/India/USA groups. He/she will fully involved in the group research, tutoring Master student figures, participating to project writing and disseminating the project results in international meetings.
Keywords: Medicinal Chemistry, Drug Design, advanced organic synthesis, Bioisosterism, NMR, MS, Molecular modeling, ADME.
The optimal candidate must be well motivated, in presence of a Master degree in Chemistry or similar and with basic experience of Practical Organic synthesis, performed during the Master thesis. Because the application is quite competitive, he/she must have acquired a top valuation during his/her Master owing a CV already enriched by some publication in Medicinal Chemistry field (also poster are counted in this case)
The project is focused on human Dihydroorotate Dehydrogenase (hDHODH), a flavin-dependent mitochondrial enzyme involved in de novo pyrimidine biosynthesis. Being already validated as a therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis,recently hDHODH was associated (Sykes et al., 2016, Cell 167, 171–186) with acute myelogenous leukemia (AML), a disease where the standard of intensive care has not changed in the last four decades. In the spring 2017, by applying a scaffold hopping approach, we described a new class of potent and selective hDHODH inhibitors based on a hydroxyazole scaffolds (Stefano Sainas et al Eu. J. Med. Chem. 2017, (129), 287-302). Following a similar strategy, in the following we introduced a novel class of inhibitors based on other hydroxyazoles systems as an unusual bioisostere of carboxylic group. The most interesting compound the series was able to reach in vitro the brequinar hDHODH potency levels. Owing low citotoxicity at cellular level, moving of leukemia cells was found able to specifically induce a massive death already at 0.1 mM, i.e., at a 1-log inferior concentration compared to brequinar. The DHODH project will be orally presented at the New Orleans American Society Meeting ACS meeting https://plan.core-apps.com/acsnola2018/abstract/8af5604b51d341b62607bc1c43442212 on March 21th, 2018
During the PhD project the candidate will move such outstanding results to in vivo AML animal models, designing a third generation of ADME optimized compounds.
The Ph.D research will be performed at MEDSynth, is a medicinal chemistry group born in the 2012 in occasion of the winning of 7FP project, at the Dept Science and Drug Technology of the University of Turin. The MEDSynth group is able to offer a complete technological platform, from the in silico design, throughout the synthesis until the in vitro / in vivo pharmacological characterization, for the design of preclinical drug candidates. See here www.medsynth.unito.it for details on out research and news.
DHODH-AML project financial support.
The hDHODH - AML project is financially supported by a three years grant inside the science and technology cooperation programme between Italy and the kingdom of Sweden (see here: https://www.esteri.it/mae/resource/garegemellaggi/2017/06/bando_italia_svezia_2018_2020.pdf, PIs Marco L. Lolli and Salam Al-Karadaghi).
Position Type: PhD program
Salary: €10'000 - €20’000.
Application opening: March 6, 2018
Application deadline: April 6, 2018
Position Category: Pharmaceutical and Bimolecular Sciences
How to apply: http://dott-sfb.campusnet.unito.it/do/home.pl
Application details: https://en.unito.it/postdegree/phd/pharmaceutical-and-biomolecular-sciences
If you think to be an eligible candidate that want to be involved in this project, please contact us sending your cv (firstname.lastname@example.org) so, in case, we can support your application. Put in the message subject” DHODH-AML PhD scholarship” so that we can immediately track you.
Marco L. Lolli