Name: DXD
Brand: BOC Sciences
Price: 1999 USD
Availability: MadeToOrder

Synonyms

N-((1S,9S)-9-Ethyl-5-fluoro-2,3,9,10,13,15-hexahydro-9-hydroxy-4-methyl-10,13-dioxo-1H,12H-benzo(de)pyrano(3',4':6,7)indolizino(1,2-b)quinolin-1-yl)-2-hydroxyacetamide

IUPAC Name

N-[(10S,23S)-10-ethyl-18-fluoro-10-hydroxy-19-methyl-5,9-dioxo-8-oxa-4,15-diazahexacyclo[14.7.1.02,14.04,13.06,11.020,24]tetracosa-1,6(11),12,14,16,18,20(24)-heptaen-23-yl]-2-hydroxyacetamide

Canonical SMILES

CCC1(C2=C(COC1=O)C(=O)N3CC4=C5C(CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)CO)O

InChI

InChI=1S/C26H24FN3O6/c1-3-26(35)15-6-19-23-13(8-30(19)24(33)14(15)10-36-25(26)34)22-17(28-20(32)9-31)5-4-12-11(2)16(27)7-18(29-23)21(12)22/h6-7,17,31,35H,3-5,8-10H2,1-2H3,(H,28,32)/t17-,26-/m0/s1

InChIKey

PLXLYXLUCNZSAA-QLXKLKPCSA-N

Density

1.57±0.1 g/cm3 (Predicted)

Solubility

Soluble in DMSO

Appearance

Solid Powder

Shipping

-20°C (International: -20°C)

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

Boiling Point

957.9±65.0°C (Predicted)

In Vitro

Dxd 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). Dxd is cytotoxic to human cancer cell lines of KPL-4, NCI-N87, SK-BR-3, and MDA-MB-468 with IC50s of 1.43 nM-4.07 nM, but the control IgG-ADC (Dxd is the payload) shows no inhibition on the four cell lines (with HER2 expression). DS-8201a (Dxd is the payload) displays significant suppression on the HER2-positive KPL-4, NCI-N87, and SK-BR-3 cell lines, with IC50 values of 26.8, 25.4, and 6.7 ng/mL, respectively, but with no such inhibition on MDA-MB-468 (IC50, >10,000 ng/mL).

In Vivo

DS-8201a (Dxd is the payload, 10 mg/kg, i.v.) shows potent antitumor activity in HER2-positive models with KPL4, JIMT-1, and Capan-1 and in HER2 low-expressing ST565 and ST313 models with HER2 IHC 1+/FISH-negative expression.

NCT Number	Condition Or Disease	Phase	Start Date	Sponsor	Status
NCT04379596	Gastric Cancer	Phase 2	2021-11-11	AstraZeneca	Recruiting
NCT05034887	Gastric Adenocarcinoma	Phase 2	2021-09-05	National Cancer Center Hospital East	Not yet recruiting
NCT04989816	Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma	Phase 2	2021-11-18	AstraZeneca	Recruiting
NCT04556773	Metastatic Breast Cancer	Phase 1	2021-11-18	AstraZeneca	Recruiting
NCT04526691	Advanced or Metastatic NSCLC	Phase 1	2021-10-22	Daiichi Sankyo, Inc.	Recruiting

DXD, short for Deruxtecan, is a sophisticated derivative of Exatecan and is predominantly acknowledged for its utilization as a payload in antibody-drug conjugates (ADCs). Characterized by its potent inhibition capabilities against DNA topoisomerase I, DXD demonstrates an impressive IC50 value of 0.31 μM, underscoring its potency. Through targeted drug delivery systems, such as ADCs, DXD offers the promise of increased efficacy and reduced systemic toxicity by directing cytotoxic activity specifically towards cancer cells that express the HER2 receptor.

The uniqueness of DXD lies in its dual functionality—its potency and its ability to be conjugated to monoclonal antibodies (mAbs). This fusion results in tailor-made ADCs that are developed to seek and bind with high specificity to cancer cells. Upon binding, the ADCs are internalized by the cancer cells, wherein the DXD is released intracellularly to exert its cytotoxic effect. The precision targeting and systemic safety profile make DXD-conjugated therapeutics a breakthrough advancement, especially notable in the targeted treatment of HER2-positive cancers, including breast cancer.

In the realm of drug discovery, DXD has catalyzed innovation by offering new pathways to tackling therapeutic challenges. The approach of creating ADCs with DXD pays homage to the concept of personalized medicine, where treatments are tailored to individual patients based on unique molecular and phenotypic characteristics. The success of DXD as a conjugated agent is exemplified by its use in ADCs such as Trastuzumab Deruxtecan (T-DXd), which has demonstrated significant clinical efficacy and has garnered approvals in various countries for the treatment of HER2-positive cancers.

From a pharmacological perspective, the action mechanism of DXD as a topoisomerase I inhibitor highlights its capability to interfere with DNA replication. This interference is particularly detrimental to rapidly proliferating cancer cells, facilitating their destruction while sparing normal, healthy cells. Such a mechanism of action not only adds a layer of effectiveness but also aligns with the current direction towards biologically rational cancer therapies that seek to exploit specific vulnerabilities of cancer cells.

The development of DXD and its integration into ADC technology underscores an era of pioneering advancements in oncology therapeutics. By continually honing in on specific molecular targets, researchers and pharmaceutical companies alike are leveraging DXD’s unique characteristics to expand the horizon for cancer treatment solutions. This, in turn, signifies a larger shift in drug discovery, where the focus is intensely tracking towards molecular precision and targeted intervention.

1.A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model

Iwata TN, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a.

2.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, Nonagase Y, Yonesaka K, Sakai K, Maenishi O, Ogitani Y, Tamura T, Nishio K, Nakagawa K, Tsurutani J

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.

3.Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology

Ogitani Y, Abe Y, Iguchi T, Yamaguchi J, Terauchi T, Kitamura M, Goto K, Goto M, Oitate M, Yukinaga H, Yabe Y, Nakada T, Masuda T, Morita K, Agatsuma T

To establish a novel and widely applicable payload-linker technology for antibody-drug conjugates (ADCs), we have focused our research on applying exatecan mesylate (DX-8951f), a potent topoisomerase I inhibitor, which exhibits extensive antitumor activity as well as significant myelotoxicity, as the payload part. Through this study, we discovered a promising exatecan derivative (DX-8951 derivative, DXd), that has the characteristics of low membrane permeability and shows considerably less myelotoxicity than that shown by exatecan mesylate in an in vitro human colony forming unit-granulocyte macrophage assay. DXd was further used for drug conjugation by using commercially or clinically useful monoclonal antibodies to evaluate the potency of the ADC. The result revealed that the DXd-ADCs targeting CD30, CD33, and CD70 were effective against each of their respective target-expressing tumor cell lines. Moreover, a novel DXd-ADC targeting B7-H3, which is a new target for ADCs, also showed potent antitumor efficacy both in vitro and in vivo. In conclusion, this study showed that this novel topoisomerase I inhibitor-based ADC technology is widely applicable to a diverse number of antibodies and is expected to mitigate myelotoxicity, thereby possibly resulting in better safety profiles than that of existing ADC technologies.

Catalog	Product Name	CAS	Inquiry
BADC-01418	C-lock-G5-Dxd
BADC-01419	C-lock-GGFG-Dxd
BADC-01440	Dxd-D5

What is DXD?

DXD is a potent cytotoxic agent commonly used in the construction of antibody-drug conjugates (ADCs). It functions by interfering with DNA replication, leading to targeted cell death. DXD’s chemical properties allow for stable conjugation to antibodies while maintaining cytotoxic activity.

4/9/2020

Could you advise how DXD is used in ADC development?

DXD is employed as a payload in ADCs, where it is chemically linked to monoclonal antibodies targeting specific antigens. This enables selective delivery of cytotoxic activity to target cells while minimizing off-target effects, supporting therapeutic precision.

28/10/2017

Could you please inform us which linkers are compatible with DXD?

DXD can be conjugated using cleavable and non-cleavable linkers. Selection depends on the desired release profile and stability requirements. Cleavable linkers allow intracellular release, while non-cleavable linkers provide enhanced stability in circulation.

2/11/2020

Good afternoon! Could you please advise what safety considerations are relevant for DXD?

Handling DXD requires stringent laboratory safety practices due to its high cytotoxicity. Appropriate personal protective equipment, containment, and adherence to regulatory guidelines are necessary to prevent accidental exposure during conjugation or experimental work.

16/4/2019

Dear BOC Sciences, how can DXD ADCs improve therapeutic outcomes?

By coupling DXD to antibodies targeting disease-specific antigens, ADCs can deliver cytotoxic agents directly to pathological cells. This targeted approach enhances efficacy, reduces systemic toxicity, and allows for controlled dosing strategies in preclinical and clinical research.

21/11/2019

— Dr. Jason Carter, Senior Scientist (USA)

DXD from BOC Sciences delivered excellent purity and consistent performance for ADC conjugation.

2/11/2020

— Dr. Olivia Bennett, ADC Chemist (UK)

Fast delivery, reliable quality, and helpful technical support. DXD was critical for our cytotoxicity assays.

21/11/2019

— Dr. Markus Klein, Medicinal Chemist (Germany)

Batch-to-batch consistency is excellent. DXD enabled smooth ADC development.

16/4/2019

— Dr. Emily Hughes, Biochemist (Canada)

High-quality DXD with detailed QC reports. Support team answered all questions efficiently.

4/9/2020

— Dr. William Adams, Lead Scientist (USA)

Reliable and consistent product. DXD facilitated our in vitro and in vivo studies.

— Dr. Sophie Morel, Research Scientist (France)

Excellent communication and dependable supply. DXD is our preferred cytotoxin source.

28/10/2017

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Size	Price	Stock	Quantity
25 mg	$1999	In stock
1 g	$23940	In stock

DXD

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