Name: Deruxtecan
Brand: BOC Sciences
Price: 649 USD
Availability: MadeToOrder

Synonyms

Deruxtecan Analog; Deruxtecan, Trastuzumab deruxtecan; DS-8201a; DS8201a; DS 8201a; Exatecan derivative; DX-8951 derivative; DX 8951; DX8951; N-[6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide

IUPAC Name

6-(2,5-dioxopyrrol-1-yl)-N-[2-[[2-[[(2S)-1-[[2-[[2-[[(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]amino]-2-oxoethoxy]methylamino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]hexanamide

Canonical SMILES

CCC1(C2=C(COC1=O)C(=O)N3CC4=C5C(CCC6=C5C(=CC(=C6C)F)N=C4C3=C2)NC(=O)COCNC(=O)CNC(=O)C(CC7=CC=CC=C7)NC(=O)CNC(=O)CNC(=O)CCCCCN8C(=O)C=CC8=O)O

InChI

InChI=1S/C52H56FN9O13/c1-3-52(73)33-19-38-48-31(24-62(38)50(71)32(33)25-75-51(52)72)47-35(14-13-30-28(2)34(53)20-36(60-48)46(30)47)58-43(67)26-74-27-57-41(65)22-56-49(70)37(18-29-10-6-4-7-11-29)59-42(66)23-55-40(64)21-54-39(63)12-8-5-9-17-61-44(68)15-16-45(61)69/h4,6-7,10-11,15-16,19-20,35,37,73H,3,5,8-9,12-14,17-18,21-27H2,1-2H3,(H,54,63)(H,55,64)(H,56,70)(H,57,65)(H,58,67)(H,59,66)/t35-,37-,52-/m0/s1

InChIKey

WXNSCLIZKHLNSG-MCZRLCSDSA-N

Density

1.48±0.1 g/cm3 (Predicted)

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

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

Boiling Point

1491.1±65.0°C (Predicted)

NCT Number	Condition Or Disease	Phase	Start Date	Sponsor	Status
NCT04526691	Advanced or Metastatic NSCLC	Phase 1	2021-10-22	Daiichi Sankyo, Inc.	Recruiting
NCT04965766	Metastatic Breast Cancer	Phase 2	2021-07-16	Gustave Roussy, Cancer Campus, Grand Paris	Recruiting
NCT05113251	Breast Neoplasms	Phase 3	2021-11-09	AstraZeneca	Recruiting
NCT04619004	Non-Small Cell Lung Cancer Metastatic	Phase 2	2021-11-15	Daiichi Sankyo, Inc.	Recruiting
NCT04622319	HER2-Positive Primary Breast Cancer	Phase 3	2021-11-05	Daiichi Sankyo, Inc.	Recruiting

Deruxtecan, a powerful antibody-drug conjugate (ADC), is designed for targeting and killing cancer cells. Here are some key applications of Deruxtecan:

Targeted Cancer Therapy: Deruxtecan is used in targeted cancer therapy to deliver cytotoxic agents directly to cancer cells while sparing healthy tissues. It is particularly effective in treating HER2-positive breast cancer by binding to the HER2 receptor and releasing its cytotoxic payload. This targeted approach minimizes systemic toxicity and enhances therapeutic efficacy.

Drug Development: Researchers employ Deruxtecan in the development of new cancer treatments, especially for tumors that express specific antigens. By conjugating different cytotoxic drugs to the monoclonal antibody component of Deruxtecan, scientists can create versatile ADCs that target a variety of cancers. This flexibility allows for the design of personalized medicine strategies tailored to individual patient profiles.

Clinical Trials: Deruxtecan is actively used in clinical trials to evaluate its safety and effectiveness in treating various types of cancer, including gastric and lung cancers. These trials are essential for gaining regulatory approval and expanding the therapeutic indications of Deruxtecan. Positive outcomes from these studies can lead to broadened clinical applications and improved patient outcomes.

Resistance Overcoming Strategies: Deruxtecan serves as a promising solution for overcoming resistance to conventional therapies. In cases where tumors have developed resistance to standard chemotherapies, Deruxtecan’s mechanism allows it to circumvent resistance pathways and effectively kill cancer cells. This application is crucial for managing refractory cancers and improving long-term survival rates.

1.[fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification

Takegawa N, Tsurutani J, Kawakami H, Yonesaka K, Kato R, Haratani K, Hayashi H, Takeda M, Nonagase Y, Maenishi O, Nakagawa K

Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel antibody-drug conjugate composed of the anti-HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of [fam-] trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to [fam-] trastuzumab deruxtecan but not to conventional HER2-targeted therapies. Furthermore, [fam-] trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2-expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that [fam-] trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.

2.HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

Rinnerthaler G, Gampenrieder SP, Greil R

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.

3.Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study

Shitara K, Iwata H, Takahashi S, Tamura K, Park H, Modi S, Tsurutani J, Kadowaki S, Yamaguchi K, Iwasa S, Saito K, Fujisaki Y, Sugihara M, Shahidi J, Doi T

BACKGROUND:Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion.

HNMR

Catalog	Product Name	CAS
BADC-01602	Trastuzumab deruxtecan	1826843-81-5
BADC-01609	Patritumab deruxtecan	2227102-46-5
BADC-01595	Datopotamab deruxtecan	2238831-60-0

What is the core chemical structure of Deruxtecan?

Deruxtecan is a key component of certain ADCs, consisting of a potent topoisomerase I inhibitor, DXd, and a cleavable tetrapeptide-based linker. The linker is designed to be stable in the bloodstream and specifically cleaved within the target cell's lysosomes, which facilitates the release of the active DXd payload.

21/4/2022

Dear team, what is the mechanism of action for the DXd payload?

DXd, a derivative of exatecan, is a potent topoisomerase I inhibitor. This mechanism differs from payloads that target microtubules. By inhibiting topoisomerase I, DXd induces DNA damage and prevents the unwinding of DNA, leading to cell cycle arrest and apoptosis. Its high potency contributes to its therapeutic efficacy.

29/12/2022

We are interested in how the Deruxtecan linker achieves controlled release.

The linker within Deruxtecan is designed to be stable until it reaches the intracellular environment of the target cell. Once internalized, lysosomal enzymes, such as cathepsins, cleave the tetrapeptide sequence. This controlled release mechanism ensures that the highly potent DXd payload is liberated precisely where it is needed, minimizing systemic toxicity.

3/7/2016

Why is maintaining a low drug-to-antibody ratio with Deruxtecan important?

The payload in Deruxtecan is highly potent and has a high drug-to-antibody ratio. This allows for more drug molecules to be delivered per antibody, amplifying the cytotoxic effect. Furthermore, the linker enables a "bystander effect," where the released payload can diffuse into and kill nearby untargeted tumor cells, increasing overall antitumor activity.

24/2/2016

Dear BOC Sciences, what are the key advantages of ADCs utilizing Deruxtecan?

ADCs employing Deruxtecan offer several key advantages, including high potency of the DXd payload, a stable linker-payload structure, and a mechanism that can induce a bystander effect. This combination of features enhances therapeutic efficacy and can overcome challenges related to antigen heterogeneity, making it a powerful platform for targeted cancer therapy.

25/6/2022

— Dr. James Parker, Senior Scientist (USA)

Deruxtecan from BOC Sciences enabled reliable payload conjugation and reproducible assay results.

3/7/2016

— Dr. Olivia Harris, ADC Chemist (UK)

We appreciated the rapid shipment and high purity of Deruxtecan for time-sensitive experiments.

25/6/2022

— Dr. Lars Fischer, Medicinal Chemist (Germany)

Batch-to-batch consistency of Deruxtecan minimized variability in our cytotoxicity studies.

24/2/2016

— Dr. Emily Carter, Biochemist (Canada)

Expert advice on Deruxtecan handling improved conjugation efficiency.