The ability to track the life journey of a drug and its interactions with our biological systems is critical to fully understanding its pharmacological activities. Whilst often overlooked, mapping a drug’s interactions with its unintended ‘off-targets’ is especially important for addressing adverse effects of drugs and identifying potential new drug targets.

Olaparib is the first PARP1/2 inhibitor approved for the targeted treatment of BRCA-mutated cancers. To delineate its pharmacological activities within the human proteome, Fillipov and co-workers developed an elegant photoaffinity labelling (PAL) approach to target-and-label protein interactors of olaparib. In this approach, the authors designed photoaffinity-based probes (AfBPs) featuring three components: (1) an olaparib-derived recognition element to ‘target’ its endogenous protein interactors (2) a diazirine photocrosslinker to ‘label’ the proteins, and (3) a pre-installed biotin for direct pull-down reporting.

With the AfBPs in hand, the authors deployed the probes for photoaffinity labelling of whole-cell protein lysates from HeLa cervical cancer cells. Whilst impermeability of the probes precludes live-cell labelling, this operationally simple approach offers a multitude of advantages over present methods. It can label protein targets using only UV irradiation as the trigger and pre-installed biotin for direct reporting. This circumvents the use of copper(I) catalysed click reactions where a secondary reporter group conjugation is required, and biocompatibility is a potential issue.

In addition to its known on-targets (PARP1 and PARP2), the photoaffinity-labelling studies revealed a broad range of previously unreported olaparib off-target interactors: 6 ADP-ribosyltransferases and 10 NAD⁺ binding proteins. Herein, the authors successfully demonstrated the applicability of bespoke photoaffinity tools for the mapping of novel pharmacological activities of an important targeted cancer drug. This method brings useful proteomic screening tools that will inform on future design of targeted therapeutics with fewer off-target complications.

Read the article.

How did you get interested in Medicinal Chemistry?

Ever since childhood, I’ve been fascinated by medicines that alleviate human ailments. Having seasonal allergies and asthma, I’ve gone through many over-the-counter and prescription medications to treat these very common conditions. The fact that a simple tablet can treat human disease remains inspiring.

What was the topic of your PhD project?

My PhD involved 2 projects. Project 1 involved the diastereoselective syntheses and anticancer evaluation of natural product-derived fluorinated sphingolipids. Project 2 involved elucidation of the molecular mechanism of chloride-sensitivity of metabotropic glutamate receptor 3 (mGluR3, class C GPCR) using molecular modelling, organic synthesis, site-directed mutagenesis, and cell signalling assays.

Where did you have your postdoc position?

For my postdoctoral work, I had the opportunity to stay at Emory Chemistry to engage in a Bristol-Myers Squibb-sponsored research project focused on developing best-in-class orally bioavailable antagonists of the CXC-type chemokine receptor 4 (CXCR4, class A GPCR) as immunomodulators to pair with immune checkpoint inhibitors.

Where are you currently working and what is your current position?

After postdoctoral fellowship, my interdisciplinary research further drove me into nucleoside antiviral drug discovery and protein-protein interaction networks in collaboration with School of Medicine colleagues in the Departments of Pharmacology & Chemical Biology, Urology, and Pathology & Laboratory Medicine. I am currently an Assistant Professor in the Emory University School of Medicine Department of Pharmacology & Chemical Biology where I am 1.5 years into building my lab.

What are your current research interests?

So many!! but my lab focuses on anticancer, antifungal, and antiviral drug discovery and delivery, protein-protein interactions disrupters and molecular glues for cancer and neurodegeneration, and location- and signalling-biased modulators of CXCR4.

How would you explain what your research area is to non-scientists?

Broadly speaking, we study the chemistry of biological localization. We seek to understand and control where and when drugs are activated in the body, where are when disease-driving protein complexes are formed, and where and when immune cells are trafficked to different tissues.

What do you like best about your work?

Through this research program, we strive, not only to develop new therapeutic approaches to treat cancer, neurodegeneration, and infectious diseases, not only to robustly contribute to the ever-growing body of human biomedical and scientific knowledge, but perhaps most importantly, to engage in training the next-generation of medicinal chemists, pharmacologists, chemical biologists, physicians, and industry leaders.

How would you describe yourself as a supervisor?

In general, I prefer to be relatively hands off. I seek to empower members of the lab to drive their own research. I typically get them up and running in the lab at the beginning, training technical laboratory skills, spectral interpretation, and laboratory safety. But once they demonstrate competence and safe laboratory practices, I encourage the team to work through their issues together. I am of course always available to discuss experiments and results, review data, edit writing materials, provide general guidance and deal with general laboratory issues. It is important to me that each member of the lab knows that I am always there for them, just an office visit, text, or phone call away if I’m not in the lab. I do not want to ever be the bottle neck for them. It is also important that each lab member grow both independently and with the team. Critical thinking, scientific planning, and experiment troubleshooting are critical components of that growth.

What do you consider your greatest achievement in your scientific career?

Reaching the level of Assistant Professor and having the opportunity to build my own lab.

Which of your papers are you most proud of and why?

I’m not sure I’ve ever thought about that before! My first 1st author paper was special of course, and a bit of a synthetic feat [DOI: 10.1021/acsmedchemlett.6b00113]. Other than that, the nucleoside therapeutics papers have been very rewarding as corresponding author [https://doi.org/10.1021/acs.jmedchem.1c01083; DOI 10.3389/fphar.2022.1083284; https://doi.org/10.1021/acsptsci.2c00252; https://doi.org/10.1021/acs.jmedchem.4c01510].

What would you like to ask from other medicinal chemists?

Medicinal chemistry is inherently a collaborative discipline, as it brings together organic synthesis, chemical & molecular biology, pharmacology, and medicine. Although the interdisciplinary nature of medicinal chemistry can make this especially challenging, it is our collective responsibility to thoroughly report reproducible methods in the literature. I am a big fan of supplementary information. In my opinion, doing the experiments is the hard part, and reporting the methods and results is the easy part. So why not report everything from the raw data, through data analysis, to the final results and related information in the SI? You’ve already troubleshot the system, so you might as well make all of your findings available so that it is easier for another lab to replicate.

Have you experienced any unfair situations during your scientific career? How would you advise scientists facing similar situations?

I have been incredibly fortunate to have great advisors and mentors during my scientific career. The one thing I will suggest is that no matter where you train or work, there will always be politics and difficult individuals. Learning how to not let those things distract you from being productive in your research, and how to effectively navigate related situations, can be very important. But no one is perfect at this, and my advice is to try and keep getting better every day.

What is the most embarrassing thing you have done in the lab while doing experiments, e.g. explosions?

One time I was quenching a bottle of n-butyllithium solution, just like they say in the safety manuals. Cannulated into addition funnel and slowly dropwise added to an ice-cold stirring solution of 10:1 hexanes:iPrOH. The addition occurred nicely without incident. However, there was some lithium salt residue remaining on the insides of the addition funnel. Feeling overconfident from having seen not even a hint of gas expulsion during the quench, I grabbed the MeOH squirt bottle to rinse down the insides. This was quickly met with violent spurting gas expulsion that thankfully did not result in a fire. But it was close.

What are your recommendations for a book, podcast, website, blog, YouTube channel or film?

I highly recommend using an RSS feed such as Feedly.com to help stay up on the recently published literature. In grad school, I would try (and often fail) to go to journal websites to reach ASAPs each week. I now subscribe to the journals I want to follow on Feedly. Feedly changed my life. It is now my home page, and I go through recently published articles on a daily basis. Derek Lowe’s In the Pipeline blog is also very good.

Which scientist do you admire most and why?

I have so much respect and admiration for chemists who became experts in the field before the advents of mass spectrometry and NMR, as well as for all researchers who didn’t have access to databases like SciFinder and search engines like Google Scholar. I don’t know what I would do without these. Also shout out to anyone who has learned a scientific discipline in a language other than your native tongue! I can only imagine how challenging this must be.