Pinophilins A (1) and B (2), new hydrogenated azaphilones, and Sch 725680 (3) were isolated from cultures of a fungus (Penicillium pinophilum Hedgcok) derived from a seaweed, and their structures were determined using spectroscopic analyses. These compounds selectively inhibited the activities of mammalian DNA polymerases (pols), A (pol γ), B (pols α, δ, and ε), and Y (pols η, ι, and κ) families, but did not influence the activities of the four X-family pols (pols β, λ, μ, and terminal deoxynucleotidyl transferase). Compound 1 was the strongest inhibitor, with IC₅₀ values of 48.6 to 55.6 μM. Kinetic analysis showed that compound 1 is a noncompetitive inhibitor of both pol α and κ activities with the DNA template-primer substrate, and a competitive inhibitor with the nucleotide substrate. In contrast, compounds 1-3 showed no effect on the activities of plant and prokaryotic pols or any other DNA metabolic enzymes tested. The compounds suppressed cell proliferation and growth in five human cancer cell lines, but had no effect on the viability of normal human cell lines.
New alkylated hydroquinones violaceoid A (1), violaceoid B (2), and violaceoid C (3), an alkylated phenol violaceoid D (4), and a cyclohexenoid violaceoid E (5) were isolated from a culture broth of Aspergillus violaceofuscus Gasperini isolated from moss. The structures were identified by interpretation of spectroscopic data (1D and 2D NMR, MS, and IR). Two known compounds, the cyclohexenoid 6 and eupenoxide (7), were also isolated. Compound 6 was isolated for the first time as a natural product and named violaceoid F. Isolated compounds were tested for cytotoxic activity against five human cancer cell lines and a mouse macrophage cell line. Violaceoid A was the most potent of the seven compounds against all cell lines. Violaceoid C and D exhibited cytotoxicity against the leukemia cell lines with LD50 values 5.9-8.3 μM, while violaceoid F was found to be cytotoxic against HCT116 and RAW264.7 with LD50 values of 6.4 and 6.5 μM, respectively. These results demonstrate that violaceoid derivatives are a new class of cytotoxic hydroquinones with a hydroxymethyl and a linear alkyl substituent.
DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity.
87 Background: DS-7300 is an antibody drug conjugate with an exatecan derivative payload that targets B7-H3, which is overexpressed in various cancers. Initial findings from an ongoing phase 1/2 dose escalation study for advanced solid tumors, and dose-expansion studies in esophageal squamous cell carcinoma and mCRPC (NCT04145622) showed that DS-7300 was generally well tolerated with early signs of clinical activity (ESMO 2021, abstract 513O). Here, we present preliminary results from the mCRPC pt subset. Methods: This study consisted of 2 parts: dose- escalation (part 1) and expansion (part 2). Part 1 assessed the safety and tolerability of DS-7300 with doses ranging from 0.8 to 16 mg/kg. A dose of 12 mg/kg was selected for part 2. Part 2 assessed safety and prospective efficacy of DS-7300 in the selected tumor types, including mCRPC. DS-7300 was administered intravenously every 3 weeks in parts 1 and 2. Results: At data cutoff (August 8, 2021), 29 pts with mCRPC from the US and Japan were enrolled in parts 1 (n = 24) and 2 (n = 5). Pts enrolled in this study were heavily pretreated, with a median of 6.0 (range, 2-10) and 5.0 (range, 3-10) prior lines of therapy in parts 1 and 2, respectively. Baseline B7-H3 expression was highly prevalent in the study population. Enrolled pts were 44 to 82 years of age (median, 68.0 years) and had an ECOG performance status ≤1. Treatment-emergent adverse events (TEAEs) occurred in 29 pts (100.0%) in parts 1 and 2, with 7 pts (21.4%) with TEAEs leading to dose interruption, 2 pts (6.9%) with TEAEs leading to dose reduction, and no pts with TEAEs associated with drug discontinuation. The most common (≥20%) all-grade (Gr) TEAEs were nausea (65.5%), infusion-related reactions (IRRs; 34.5%), fatigue (34.5%), chills (31.0%), vomiting (31.0%), anemia (27.6%), diarrhea (27.6%), and dehydration (20.7%). Gr ≥3 TEAEs occurred in 10 pts (34.5%); the most common was anemia (17.2%). There were no Gr ≥3 treatment-related serious TEAEs (SAEs) reported. All IRR cases were Gr 1/2 and manageable with supportive care. No ILD/pneumonitis cases were reported. RECIST responses were observed in pts treated with DS-7300 between 6.4- and 16.0-mg/kg doses, including 6 partial responses (4 confirmed) and 15 stable diseases. The median duration of treatment was 13.9 weeks (range, 3-40 weeks) in part 1 and 6.0 weeks (range, 3-9.14 weeks) in part 2. At data cutoff, 8 pts (66.7%) in the 12.0-mg/kg group in part 1 and 4 pts (80.0%) in part 2 were ongoing treatment. Moreover, preliminary data indicate improvements in prostate-specific antigen (PSA) and bone metastases. Conclusions: DS-7300 was well tolerated with an acceptable safety profile in pts with mCRPC. The preliminary safety and efficacy data are encouraging and warrant further investigation. Clinical trial information: NCT04145622.
TPS3646 Background: B7 homologue 3 (B7-H3) is a protein that is overexpressed in various cancer types, including lung, head and neck squamous cell carcinoma, prostate, esophageal, and breast. B7-H3 overexpression is associated with poor prognosis because it promotes increased invasive and metastatic potential of cancer cells (Dong P, et al. Front Oncol. 2018;8:264). Currently, no B7-H3–targeted cancer therapies are approved. DS-7300a is an antibody-drug conjugate composed of a humanized anti–B7-H3 IgG1 monoclonal antibody (MABX-9001a) conjugated to a drug linker that releases its payload upon internalization by cancer cells. The payload, DXd, is an exatecan derivative that inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA for replication and transcription. DS-7300a induced apoptosis in cancer cells in vitro and showed potent antitumor activity in xenograft models of various types of solid tumors in vivo. Methods: This phase 1/2, multicenter, nonrandomized, open-label, first-in-human study of DS-7300a is ongoing in the United States and Japan in patients with selected advanced solid tumors (NCT04145622). This study has 2 parts: dose escalation (part 1) and dose expansion (part 2). Primary objectives are to evaluate the safety, tolerability, and antitumor activity of DS-7300a and to determine the maximum tolerated dose or recommended dose for the expansion part. Secondary objectives include the pharmacokinetic characterization of DS-7300a, determination of the total levels of anti–B7-H3 antibody and the drug component (DXd), and assessment of the incidence of anti-drug antibodies against DS-7300a. Key inclusion criteria are age ≥ 18 years (United States) or ≥ 20 years (Japan), an ECOG performance status of 0 or 1, ≥ 1 measurable lesion according to RECIST 1.1 as assessed by the investigator, and consent to provide pre- and on-treatment tissue samples (mandatory if clinically allowed and not contraindicated). Key exclusion criteria include prior treatment with orlotamab, enoblituzumab, other B7-H3–targeted agents, or an antibody-drug conjugate that is conjugated with a topoisomerase I inhibitor. Dose expansion will start with 3 cohorts, including patients with selected advanced solid tumors. In both parts, DS-7300a will be administered intravenously on day 1 of each 21-day cycle. During dose escalation, the starting dose of DS-7300a is 0.8 mg/kg. This trial is currently in the dose-escalation part. Clinical trial information: NCT04145622 .
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