In This Issue, Volume 10, Issue 10

Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aβ Peptides

Alzheimer’s disease, the most common form of dementia, is characterized by plaques in the brain composed of 40 and 42 residue peptide amyloids, Aβ40 and Aβ42, respectively. Aβ is produced through the processing of the neuronal amyloid precursor protein (APP) by the β- and γ-secretase proteases (BACE1 and γ-secretase, respectively). However, to date, BACE1 and γ-secretase inhibitors have failed in the clinic. In this Letter, Sinha et al. (DOI: 10.1021/acsmedchemlett.9b00213) follow up on their previous results that showed Gleevec and a kinase-inactive inhibitor DV2-103 effectively reduced Aβ40 and Aβ42 levels as a novel mode of action of these inhibitors. Here, the authors produce a library of analogs of DV2-103 to understand the structure–activity relationship. Nine compounds showed improved or comparable levels of efficacy for reducing Aβ levels, while still maintaining reduced kinase activity. Mechanistic studies supported a mode of action of these compounds similar to Gleevec and DV2-103, leading to altered processing of full length APP. Importantly, the effects of these compounds were also synergistic when combined with a BACE1 inhibitor. Future studies seek to further explore the synergy studies of these new analogs with BACE1 inhibitors and to evaluate potential toxic effects of the alternatively processed APP peptides.

N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity

Due to the growing number of drug-resistant microorganisms, there is an urgent need for the discovery of new chemical entities with antibiotic activity. Historically, sulfur- and fluorine-containing molecules have played a significant role in the design of new drug substances. Currently, the prevalence of fluorinated functional groups in bioactive substances continues to increase based on the availability of new synthetic methods and both the stability and physicochemical property modulation afforded by fluorination. In this Letter, Thota et al. (DOI: 10.1021/acsmedchemlett.9b00285) develop a new synthetic N-trifluoromethylthiolation strategy to generate a focused library of N-trifluoromethylthio sulfonimidamides and sulfoximines. Whereas thiotrifluoromethyl (SCF₃) groups are found in many bioactive substances, these functional groups remained unexplored. In the first report of the bioactivity of these N-SCF₃-containing molecules, the authors find significant antimycobacterial activity against M. tuberculosis. However, cytotoxicity was also observed in a model cancer cell line. Through a paired analysis with N-CF₃-containing analogs, the authors attribute the general toxicity to the -SCF₃ group. Despite the significant use of -SCF₃ groups in drug design, these results highlight a potential unexpected liability from this novel fluorinated functional group.

Preclinical Development of PQR514, A Highly Potent PI3K Inhibitor Bearing a Difluoromethyl–Pyrimidine Moiety

Inhibitors of the phosphoinositide 3-kinase (PI3K) and downstream mechanistic target of rapamycin (mTOR) are of clinical interest due to the role of this signaling pathway in cancer and neurodegenerative diseases. Over 200 clinical trials are currently underway targeting PI3K signaling. PIQUR Therapeutics’s clinical candidate, PQR309 (bimialisib), is based on a triazine-linked trifluoromethylpyridine scaffold and possesses a dual mode of action against PI3K and mTOR. Bimialisib is currently in Phase II clinical trials for lymphoma and solid tumors. In this Letter, Borsari et al. (DOI: 10.1021/acsmedchemlett.9b00333) disclose an improved design in which a trifluoromethyl to difluoromethyl substitution was made as a potential mechanism for tuning an active-site hydrogen bond. In addition, a pyrimidine was substituted for the pyridine. These changes improved PI3K inhibition by 8-fold and mTOR inhibition ∼2-fold leading to a novel and improved anticancer agent, PQR514. This compound demonstrates high selectivity for PI3K α/β/γ/δ and was highly active across 66 tumor cells. In vivo administration demonstrated on-target activity and significant antiproliferative effects in ovarian cancer mouse xenograft studies. Importantly, greater tumor reduction for PQR514 was observed than for clinical candidate bimialisib at an eight-times lower dose. Both the pharmacological activity and safety profile support PQR514 as a new anticancer drug candidate.