Arjan van Adrichem's doctoral thesis demonstrates that there is no such thing as an impossible drug target

Members of the guanine triphosphatase (GTPase) protein families are important regulators of various essential cellular pathways. Many of them are associated with cancer, inflammatory and neurodegenerative disorders and are thus attractive drug targets. Not only are GTPase proteins hard to target due to their very smooth surface, but because they have so many important regulatory functions, targeting these enzymes directly is expected to lead to unspecific and severe side effects. Consequently, only very few clinically relevant GTPase targeting drugs are available to date.

In his thesis, to be examined publically tomorrow 9 September, M.Sc. Arjan van Adrichem tackled this problem by taking an alternative approach and focusing on proteins that regulate GTPases, such as GTPase activating proteins (GAPs). When GTPase regulatory proteins instead of the GTPases themselves are targeted, a much more specific inhibition of selected cellular signaling pathways can be expected. No drugs targeting these proteins were available when he started his thesis project.

Arjan’s thesis is entitled "Discovery of Small Molecule Modulators of Ras Superfamily Proteins – Studies of MgcRacGAP and Ras” and he did the work at FIMM in the group of FIMM-EMBL Group Leader Krister Wennerberg with Dr. Outi Monni providing guidance throughout the project.

Arjan graduated from the Eindhoven University of Technology in 2010, majoring in medical engineering. During this time he was interested in gaining a deeper understanding about medical research and his mentor suggested an internship in one of the Nordic countries. Krister Wennerberg welcomed him to FIMM in the spring of 2010 and soon a short internship turned into a full-length Doctoral thesis project. 

Despite the challenges I have encountered during this project, I have never regretted the decision to stay at FIMM and do my PhD here. I have enjoyed both the freedom and the support that FIMM and my group have provided.

- Arjan van Adrichem

Small molecule with big potential

The main aim of Arjan’s thesis was to identify new small molecule modulators specifically targeting GTPase regulatory proteins through different high-throughput screening approaches. By utilizing these molecules he then wanted to improve the understanding of the function and regulation of a subclass of the Ras superfamily of small GTPases, called the Rho GTPase family.

Arjan’s thesis consists of three publications. All, especially the first one, are exceptionally broad, utilize many different techniques and approach the topic in a systematical and comprehensive way.

The most important finding of his thesis is the identification of a molecule called MINC1 as a specific inhibitor of a certain GTPase-activator, MgcRacGAP. Arjan was the first in the world to successfully target such a protein and thus to prove that they are both screenable and druggable.

I have always wanted to know how things - or cells - work. Finding a new, significant piece of the puzzle truly motivates me, even more than the greater goals such as curing cancer.

Developing and designing the assays and screening methodology was an important and time-consuming part of Arjan’s thesis work and Arjan hopes that these methodologies will be used by others when designing future studies with other small GTPase activating proteins.

The protein I have been working with for many years turned out to be a very puzzling target. Of the over 360 000 compounds we tested, MINC1 was the only potential hit and none of the analogs we have tested thus far perform better. The compound wasn’t available anywhere in the world for our future studies and synthesizing it became a new thesis project for one of our collaborators!

Arjan will turn a new page in his career right after his thesis defense. He and his Finnish wife and their newborn son will move to the Netherlands where Arjan will participate in a training program in Hospital Zuyderland MC to become a clinical chemist.

The public examination of Arjan van Adrichem’s doctoral dissertation entitled “Discovery of small molecule modulators of Ras superfamily proteins - Studies of MgcRacGAP and Ras" will take place in Lecture hall 1, Haartman Institute, on 9 September 2016 at 12:00. Professor Xosé Bustelo (Cancer Research Center, University of Salamanca, Spain) will serve as the opponent and Professor Satu Mustjoki as the custos.

The dissertation is also available in electronic form through the E-thesis service.