FIGON DMD

Khaled Essa

Leiden University

Khaled holds a Bachelor's degree in Pharmaceutical Sciences from Utrecht University (2015-2018) and pursued an international master's program in Innovative Medicine through the Erasmus Mundus Scholarship at the University of Groningen, Netherlands, and Uppsala University, Sweden (2018-2020). Currently a third-year PhD candidate at Leiden University, Netherlands, under the supervision of Prof.Laura Heitman (since 2021).

Khaled carried out internships in the Drug Design Group at the University of Groningen, where he focused on utilizing multicomponent chemistry for degrader development. Additionally, he explored novel photoredox catalytic methods for the synthesis of bioactive molecules at Bayer AG, Wuppertal, Germany.

His current research focus lies in the discovery and development of novel therapeutic modalities targeting class A G protein-coupled receptors (GPCRs).

Presentation: Exploration of targeted CCR2 degradation as a novel therapeutic modality

Authors: Khaled Essa, Natalia Ortiz, Benthe Bleijs, Richard de Heiden, Bo Tao, Monique Mulder, Huib Ovaa, Daan van der Es, Laura Heitman.

CC-chemokine receptor 2 (CCR2) is a class A GPCR that plays a crucial role in trafficking of leukocytes to inflammatory sites. Dysregulation of the CCR2 signaling axis through overactivation and/or overexpression of CCR2 is implicated in multiple immunoinflammatory indications and cancers. None of the discovered clinical candidates succeeded due to failure to meet clinical endpoints.

We hypothesized that developing proteolysis targeting chimeras (PROTACs) for CCR2 could pose as an alternative approach to drug the yet undruggable CCR2. Accordingly, we designed CCR2 PROTACs that employed a previously discovered intracellular allosteric CCR2 inhibitor (1) and E3 ligase ligands to hijack VHL, MDM2 and CRBN connected by various linkers.

Radioligand binding assays confirmed that CRBN-recruiting CCR2 PROTACs maintained efficient binding to CCR2. Using an xCELLigence assay, we demonstrated that only CRBN-recruiting CCR2 PROTACs displayed sufficient membrane permeability. The degradative capacity of the CRBN-recruiting PROTACs was then assessed in a real-time HiBit assay, where four PROTACs (LUF7995, 7996, 8062, and 8063) demonstrated a dose-dependent degradation of CCR2.

Collectively, four novel CCR2 degraders have been identified. The results of this study highlight a potential alternative to drugging CCR2 and provides a pipeline of assays that can be utilized to evaluate other novel GPCR degraders.