EFMC Prize for a Young Medicinal Chemist or Chemical Biologist in Industry

Nominations should be written by the candidate’s supervisor and consist of:

• a letter by the supervisor.
• a brief candidate CV.
• an abstract of the potential oral presentation.

EFMC Prize for a Young Medicinal Chemist or Chemical Biologist in Academia

Applications should consist of:

• a one-page letter by the candidate, including a short rationale for their application.
• one page with five key publications.
• a brief candidate CV.
• an abstract of the potential oral presentation.

“Read more”

Heterobifunctional molecules such as PROTACs and multitarget compounds have emerged as promising modalities against challenging targets and diseases, and particularly promising for cancer treatment. In this article, R. C. Bizga Nicolescu et al. develop conjugate molecules comprising two androgen receptor (AR) inhibitors to treat metastatic pancreatic cancer (PCa).

Patients with PCa that develop metastasis are often treated with androgen-deprivation therapy, but often progress to a more advanced and often incurable stage known as Castration-Resistant Prostate Cancer (CRPC). They then receive second generation AR inhibitors such as enzalutamide or other steroidal and non-steroidal anti-androgens. However, development of resistance to these inhibitors is common, which often occurs through the formation of AR variants (AR-Vs) that lack the AR ligand-binding domain (LBD) where enzalutamide binds. To address this limitation, another class of inhibitors has been developed to target the alternative N-terminal domain (NTD); these contain a bisphenol A core structure and are known as EPI analogues. Even though EPI analogues such as EPI-001 can inhibit AR-Vs lacking the LBD, they display poor pharmacokinetic properties and have low potency.

To circumvent the limitations of the known AR inhibitors, R. C. Bizga Nicolescu et al. developed hybrid compounds that simultaneously target both sites of the AR, i.e., LBD and NTD. The authors prepared five analogues containing enzalutamide and EPI-001 covalently linked with different triazole-PEG linkers. In C4-2b, a metastatic prostate cancer cell line expressing several AR-Vs, their conjugates displayed up to 53-fold improvement of LC₅₀ compared to the initial inhibitors alone or in combination. On the other hand, smaller effects were observed for some of their molecules in PC-3 cells, which express very low levels of AR-Vs, supporting their AR-dependent toxicity. Their top compound 9b had an LC₅₀ of 1.6 µM in C4-2b cells but >75% viability at 10 µM in PC-3 cells. The authors hypothesise that the enhanced potency of the conjugates, as compared to a combination of the original inhibitors, could be due to an entropic effect, where the linker may be increasing the effective local concentration of the second inhibitor.

The team then proved interaction of some of the compounds with AR. Firstly, 9b inhibited AR-mediated transcriptional activity in a luciferase assay. Secondly, RT-qPCR experiments showed that 9e inhibited expression levels of the KLK3 gene, which is tightly regulated by the AR. In these assays the compounds were found to be less potent than enzalutamide, most likely due to lower membrane permeability.

In conclusion, the authors developed a first-in-class AR inhibitor 9b that circumvents some of the limitations of current clinical drugs for aggressive stages of PCa.

Bizga Nicolescu, R. C., Maylin, Z., Perez Areales, F. J., Iegre, J., Pandha, H., Asim, M., & Spring, D. R. (2022). Hybrid androgen receptor inhibitors outperform enzalutamide and EPI''.chr('8208').''001 in in vitro models of prostate cancer drug resistance. ChemMedChem. doi:10.1002/cmdc.202200548

https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202200548

• 17th EFMC Short Course on Medicinal Chemistry: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development
  Oegsgeest, The Netherlands | April 23-26, 2023
  www.efmcshortcourses.org
  Deadline for application: January 25, 2023

• ACSMEDI-EFMC Medicinal Chemistry Frontiers 2023
  Boston, United States | June 10-13, 2023 
  www.medchemfrontiers.org
  Deadline for application: February 15, 2023

• IX EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry (EFMC-ASMC 2023)
  Zagreb, Croatia | September 3-7, 2023 
  www.efmc-asmc.org
  Deadline for application: March 15, 2023

• 10th EFMC Young Medicinal Chemists' Symposium (EFMC-YMCS 2023)
  Zagreb, Croatia | September 7-8, 2023 - Nice, France
  www.efmc-ymcs.org
  Combined with the grant application of EFMC-ASMC 2023 (Participation to both events is mandatory)

• EFMC International Symposium on Chemical Biology (EFMC-ISCB 2023)
  Basel, Switzerland | November 16-18, 2023
  www.efmc-iscb.org
  Deadline for application: March 30, 2023

Once registered in the grant system, you will receive a confirmation email with your data to access your secured page, and upload the following:

• Cover letter
• Support letter by the supervisor
• CV
• Publications' List
• Abstract of the Oral Communication/Poster Presentation (not required for the EFMC Short Course)

Please be informed that following EFMC regulations, only the members of an EFMC National Adhering Organisation will be allowed to apply for the EFMC grants.

• Prof. Rui Moreira (University of Lisbon, Portugal) – President
• Dr Luc Van Hijfte (Symeres, The Netherlands) – President Elect
• Prof. Gianluca Sbardella (University of Salerno, Italy) – Secretary
• Prof. Christa Müller (University of Bonn, Germany) – Member

EFMC would also like to sincerely thank Dr Yves Auberson (Novartis, Switzerland), Prof. Anders Karlén (Uppsala University, Sweden) and Dr Antoni Torrens (WeLab, Spain) for their contribution as executive committee members for the past years.