Pharmacological targeting of lipid metabolism by a first-in-class SREBP-targeted degrader to treat glioblastoma.
Authors: Ham Seok Won , Kim Jun-Kyum , Kim Hyejin , Kim Eun-Jung , Park Cheol Gyu , Lee Su-Jeong , Lee Sang-Koo , Park Min Gi , Park Jong Min , Yoo Seung Jun 
Published: June 2024

2038 Background: Glioblastoma (GBM) is an incurable cancer. Patients are subjected to inevitable death by recurrence after the standard treatment, temozolomide (TMZ) and irradiation. Having the tumor-initiating ability, GBM cancer stem cells (GSCs) resist standard therapy and give rise to recurrent tumors; however, no GSC-targeted treatment has proven its efficacy in clinical trials. Therefore, we sought to discover the vulnerability of GSCs and develop a novel targeted therapy to combine with TMZ, which will enable the complete treatment of GBM without the risk of relapse. Methods: We assessed the datasets of GBM patients and patient-derived GSCs to discover the signaling pathways enriched in GSCs that are specifically sensitive to dysregulation. We conducted transcriptomic, metabolomic and cellular assays to verify the essentiality of the pathway in GSCs and to find the target suitable for disturbing the pathway pharmacologically. Through the chemical library screening and chemical optimization, we developed a novel compound that specifically degrades the target. We validated the on-target specificity and pharmacokinetic (PK) properties through biological and pharmacological studies. We verified the anti-cancer efficacy in combination with TMZ using the GBM orthotopic xenograft mouse model and evaluated the safety and toxicity by non-clinical assessments. Results: Unbiased analysis using the datasets of patients and GSCs revealed that ABCA3-related lipid metabolism is enriched in GSCs compared to non-GSCs. ABCA3 knockdown caused the disturbance in lipid metabolic homeostasis, leading to a decrease in the sterol-regulatory element binding protein 1 (SREBP1) activity to suppress the tumor-initiating capacity of the GSCs. We developed MFC0101, a novel small molecular compound to target the SREBP1 signaling pathway. MFC0101 specifically engages the SREBP cleavage-activating protein (SCAP), which binds to and stabilizes the SREBP1 protein, to block the protein-protein interaction between SCAP and SREBP1, inducing the degradation of SREBP1. MFC0101 displayed favorable PK profiles, such as high oral bioavailability (greater than 50% in dogs, rats, and mice) and blood-brain barrier permeability (brain-to-plasma ratio of 0.543 based on exposure in mice). MFC0101 showed no adverse events, even at the dose level required to reach maximal systemic exposure in the 28-day toxicity study in rats, and no geno- and cardiovascular toxicities. Notably, MFC0101, combined with TMZ, showed greater efficacy than TMZ alone in the GBM mouse model; 87.5% and 100% displayed complete remission of the tumor after the treatment of medium and high dose levels of MFC0101, respectively (n ≥ 8 per group). Conclusions: MFC0101, the first-in-class SREBP1-targeted degrader, demonstrates its outstanding preclinical efficacy in synergy with TMZ and reasonable safety as a promising GBM treatment.