Activating mutations in the gene are important targets in cancer therapy because they are key drivers of non-small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations..

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The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure–activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1H-indol-1-yl)­benzamide structure. The pyrazolo­[3,4-b]­pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.

A biomimetic pathway to lucilactaene (1) from NG‐391 has been developed which involves stereoselective reactions under very mild conditions. It was demonstrated that 1 racemizes rapidly, and the conditions under which racemization occurs were elucidated. Lucilactaene (1) isolated under neutral conditions is racemic, which suggests that either the natural product is racemized rapidly in the mycelia, or racemic 1 is biosynthesized.

Ein biomimetischer Weg führt unter sehr milden Bedingungen stereoselektiv von NG‐391 zu Lucilactaen (1). Es wurde gezeigt, dass 1 rasch racemisiert, und die Bedingungen, unter denen Racemisierung eintritt, wurden aufgeklärt. Lucilactaen (1), das unter neutralen Bedingungen isoliert wird, ist racemisch, was dafür spricht, dass entweder der Naturstoff in den Mycelien rasch racemisiert oder bei der Biosynthese racemisches 1 entsteht.