In This Issue, Volume 14, Issue 2

Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

Use of proteolysis targeting chimeras (PROTACs) is an innovative approach developed to silence a specific target from the biological environment. PROTACs are heterobifunctional conjugates of a ligand that binds to the target protein of interest with a second ligand for an E3 ligase system. Once formed, a ternary complex between an E3 ubiquitin ligase polyubiquitinates the target protein, causing its degradation by the proteasome.

In this issue, Jarusiewicz et al. (DOI: 10.1021/acsmedchemlett.2c00436) prepared and analyzed novel cereblon ligands endowed with favorable pharmacokinetic (PK) and stability properties. Due to the chemical instability of thalidomide derivatives in in vitro assays, including imide hydrolysis and racemization, the authors previously synthesized a family of phenyl glutarimide (PG)-containing compounds which demonstrated a high affinity for E3 ligase and improved stability. Nevertheless, the drawback of the PG series is their propensity to still racemize, resulting in a reduction in potency due to the inactivity of the S-enantiomer. To overcome the racemization issue, the authors replaced the PG component with an achiral phenyl dihydrouracil (PD)-based moiety. Three different PROTAC systems were synthesized while maintaining dasatinib as the LCK ligand and different E3 ligands and linkers for comparative studies. Cereblon affinity, chemical stability, target degradation, and cytotoxicity were assessed. PD-PROTACs exhibited only a modest reduction in cereblon affinity but displayed improved chemical stability compared to PG analogs. The good stability values increased the cellular degradation of LCK and the antiproliferative activity on KOPT-K1 cells, leading to the most potent LCK degrader to date. ADME analysis revealed acceptable active permeability but low microsomal stability. High metabolic clearance remains a liability for this compound class, including parent molecule dasatinib. This study provides more design principles on cereblon ligands and offers new insights for improving PROTACs.

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor

Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant non-Hodgkin lymphoma (NHL) that affects B-lymphocytes. Although DLBCLs can develop at any age, they are more frequent in older people. Despite the success of frontline therapy, due to tumor heterogeneity, novel targeted therapies are required.

In this issue, Mamai and co-workers (DOI: 10.1021/acsmedchemlett.2c00502) disclose the identification of OICR12694/JNJ-65234637, a BCL6-BTB inhibitor that exhibits potent antiproliferative activity against DLCBL cells and excellent oral bioavailability. Starting from a series of previously reported BCL6 inhibitors, the authors efficiently performed a virtual screen and tested the top-scoring compounds in a surface plasmon resonance assay. The screening campaign led to the identification of a novel pyrrolopyridone hit structure with inhibitory activity in the high micromolar range. Further optimization and co-crystal structures of analogs with the BCL6 BTB domain resulted in the synthesis of a series of tricyclic C3-substituted pyrrolopyrimidinones with potent biochemical and nanomolar cellular activity. ADME analysis revealed good microsomal stability and high active permeability. Pharmacokinetic studies in both mouse and dog models confirmed good oral bioavailability. The absence of genotoxicity and the minimal inhibition of the hERG channel highlighted the success of the optimization campaign.

Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is a complex neurological pathology with a multifactorial origin. It is marked by tremors and bradykinesia. While the exact molecular causes of PD are still unknown, various cellular processes and genes have been linked to its progression. One process includes the loss of function of the glucosylcerebrosidase (GBA) gene, leading to central nervous system (CNS) accumulation of glucosylceramide and glucosylsphingosine.

In this issue, Roecker and co-workers from Merck (DOI: 10.1021/acsmedchemlett.2c00441) describe the identification of novel small molecules that block glucosylceramide synthase (GCS). Starting from a hit previously disclosed from a high-throughput screening campaign and characterized by suboptimal potency but excellent CNS permeability, the authors carried out extensive structure–activity relationship studies. To enrich the possibility of CNS penetration, the internal library was filtered with a CNS multiparameter score function, and permeability and P-gp efflux were taken into consideration from the first phases of analysis. The optimization protocol resulted in a novel series of potent compounds. The absence of CYP and hERG inhibition, coupled with good in vitro ADME, led the authors to perform in vivo pharmacokinetic and pharmacodynamic studies. The lead compound demonstrated a statistically relevant dose-dependent reduction of GlcCer in C57 black mice, reaching the highest effect at a dose of 100 mg/kg. Overall, this paper described a novel scaffold that inhibits GCS in mice and introduced new molecular tools to better understand GSC biology in in vivo and ex vivo models.