In This Issue, Volume 14, Issue 1

Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells

Among all mitogen-activated protein kinase (MAPK) signal transduction pathways, the Raf/MEK/ERK pathway is the most crucial signaling cascade and plays a major role in cell proliferation and survival. Two closely related isoforms, MEK1 and MEK2, are ubiquitously expressed, non-receptor proteins that play a key role in the MAPK signaling cascade. Numerous efforts have led to the identification of selective MEK1/2 inhibitors, including four FDA-approved drugs. Despite these advances, acquired resistance to MEK1/2 inhibitors invariably develops. Thus, MEK1/2 degradation via proteolysis targeting chimeras (PROTACs) has emerged as an attractive approach to overcome resistance.

In this Letter (DOI: 10.1021/acsmedchemlett.2c00446), Ping Xu and colleagues reported the use of the hetero-bifunctional PROTAC degrading platform to identify potent MEK1/2 degraders using a coumarin-based inhibitor scaffold targeting an allosteric site. Inspired by previously reported, diarylamine-based MEK1/2 degraders, the authors designed and synthesized a series MEK PROTACs using an established MEK inhibitor scaffold from their own lab and others containing a coumarin as a target warhead and CRBN or VHL as the E3 ligase. Using molecular docking, the arylamino group of the MEK inhibitor was identified as the site for substitution of the PROTAC linker and E3 ligase binding ligand. Further SAR and linker optimization led to the identification of MEK1 and MEK2 degrader P6b with potent in vitro activity in cancer cells.

Sulfonamide Prodrugs with a Two-Stage Release Mechanism for the Efficient Delivery of the TLR4 Antagonist TAK-242

Organ transplant rejection, where the immune system attacks the host or transplanted tissue, remains the primary cause of mortality in transplant patients. Controlled and localized immunomodulator drug delivery is an attractive and effective strategy to protect transplant tissue from damage caused by acute allograft rejection.

In this issue (DOI: 10.1021/acsmedchemlett.2c00492), Robert Kane and co-workers disclose the design and synthesis of second-generation prodrug TLR4 antagonists based on TAK-242. Further, these authors demonstrate via kinetics studies that the prodrugs achieve a clean release of TAK-242 without the side reactions that were observed with their first-generation prototype. The earlier versions of a TAK-242 prodrug suffered unproductive sulfonamide hydrolysis that was competitive with the desired β-elimination and drug release. Thus, the authors evaluated a series of prodrug cores, along with a broad range of trigger moieties with varied release kinetics. Key features of the newly designed prodrug included four required elements: TAK-242 connected through an aminobenzyl spacer to two N-linked regions for a synthetic bioconjugation handle and a β-elimination component. Ultimately this design permitted distinct phases of disassembly that reduced side reactions. Release kinetics studies of the prodrug derivatives led to the characterization of their rapid, intermediate, and slow drug release rates. This work clearly shows that these new TAK-242 prodrugs cleanly released the TLR4 antagonist without unwanted side reactions.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist

Somatotropin release inhibiting factors (SRIFs, somatostatins) are a family of peptide hormones formed by gastrointestinal, immune, endocrine, and neuronal cells. Somatostatin SRIF-14 is a highly potent cyclopeptide that regulates multiple biological processes through interactions with five SRIF receptor subtypes (SST1–SST5). These effects formed the basis for the discovery of synthetic peptide analogues of SS14, such as octreotide for the treatment of acromegaly and neuroendocrine tumors (NETs). However, despite earlier clinical success of these peptides, there still remains a need for better molecules due to poor bioavailability and a complicated mode of administration.

In this issue (DOI: 10.1021/acsmedchemlett.2c00431), Stephen Betz and co-workers disclose the discovery of novel and potent SST2 agonists with excellent SRIF receptor subtype selectivity. The authors’ lead compound identification effort began with the evaluation of a focused library with novel scaffolds, followed by lead optimization and SAR studies to identify the 4-(4-aminopiperidinyl)-3,6-diarylquinoline series (including compound 22 and its analog 24) as potent SST2 agonists. Further in vitro selectivity and ADME studies of these compounds revealed 22 and 24 as metabolically stable candidates. Compound 22 (Paltusotine) was selected as the clinical candidate due to its excellent in vivo bioavailability profile and is currently in Phase 2 and 3 trials for treating NETs and acromegaly, respectively.