CAS No. : 1599440-33-1

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Cat No:T000055
Molecular Formula:C26H24FN3O6
Molecular Weight:493.5
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Cat No:T000055
Cas No:1599440-33-1
IUPAC Name:N-[(10S,23S)-10-ethyl-18-fluoro-10-hydroxy-19-methyl-5,9-dioxo-8-oxa-4,15-diazahexacyclo[,14.04,13.06,11.020,24]tetracosa-1,6(11),12,14,16,18,20(24)-heptaen-23-yl]-2-hydroxyacetamide
Dxd (cas 1599440-33-1) is a potent DNA topoisomerase I inhibitor, with an IC50 of 0.31 μM, used as a conjugated drug of HER2-targeting ADC (DS-8201a). 
1. Clin Cancer Res. 2016 Oct 15;22(20):5097-5108. doi: 10.1158/1078-0432.CCR-15-2822. Epub 2016 Mar 29.
DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.
Ogitani Y(1), Aida T(2), Hagihara K(2), Yamaguchi J(2), Ishii C(2), Harada N(2), Soma M(2), Okamoto H(2), Oitate M(2), Arakawa S(2), Hirai T(3), Atsumi R(2), Nakada T(2), Hayakawa I(2), Abe Y(2), Agatsuma T(2).
Author information:
(1)Daiichi Sankyo Co., Ltd., Tokyo, Japan. [email protected] (2)Daiichi Sankyo Co., Ltd., Tokyo, Japan. (3)Clinical Development Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
PURPOSE: An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed.
EXPERIMENTAL DESIGN: In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.
RESULTS: DS-8201a exhibited a HER2 expression-dependent cell growth-inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression.
CONCLUSIONS: DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1-insensitive HER2-positive cancers and low HER2-expressing cancers. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

2. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. doi: 10.1248/cpb.c18-00744.
The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy.
Nakada T(1), Sugihara K(1), Jikoh T(1), Abe Y(1), Agatsuma T(1).
Author information:
(1)Research and Development Division, Daiichi Sankyo Co., Ltd.
A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody-drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

3. Int J Cancer. 2017 Oct 15;141(8):1682-1689. doi: 10.1002/ijc.30870. Epub 2017 Jul 12.
DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance.
Takegawa N(1), Nonagase Y(1), Yonesaka K(1), Sakai K(2), Maenishi O(3), Ogitani Y(4), Tamura T(1), Nishio K(2), Nakagawa K(1), Tsurutani J(1).
Author information:
(1)Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan. (2)Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan. (3)Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan.
(4)Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan.
Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.

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