Name: DM1-SMCC
Brand: BOC Sciences
Price: 298 USD
Availability: MadeToOrder

Synonyms

2,5-dioxopyrrolidin-1-yl 4-((3-((3-(((2S)-1-(((14S,16S,33S,2R,4R,10E,12Z,14R)-86-chloro-14-hydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-12,6-dioxo-7-aza-1(6,4)-oxazinana-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-4-yl)oxy)-1-oxopropan-2-yl)(methyl)amino)-3-oxopropyl)thio)-2,5-dioxopyrrolidin-1-yl)methyl)cyclohexane-1-carboxylate; DM1 SMCC; SMCC-DM1

IUPAC Name

(2,5-dioxopyrrolidin-1-yl) 4-[[3-[3-[[(2S)-1-[[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl]oxy]-1-oxopropan-2-yl]-methylamino]-3-oxopropyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]methyl]cyclohexane-1-carboxylate

Canonical SMILES

CC1C2CC(C(C=CC=C(CC3=CC(=C(C(=C3)OC)Cl)N(C(=O)CC(C4(C1O4)C)OC(=O)C(C)N(C)C(=O)CCSC5CC(=O)N(C5=O)CC6CCC(CC6)C(=O)ON7C(=O)CCC7=O)C)C)OC)(NC(=O)O2)O

InChI

InChI=1S/C51H66ClN5O16S/c1-27-10-9-11-37(69-8)51(67)25-35(70-49(66)53-51)28(2)45-50(4,72-45)38(24-42(61)55(6)33-21-31(20-27)22-34(68-7)44(33)52)71-47(64)29(3)54(5)39(58)18-19-74-36-23-43(62)56(46(36)63)26-30-12-14-32(15-13-30)48(65)73-57-40(59)16-17-41(57)60/h9-11,21-22,28-30,32,35-38,45,67H,12-20,23-26H2,1-8H3,(H,53,66)/b11-9+,27-10+/t28-,29+,30?,32?,35+,36?,37-,38+,45+,50+,51+/m1/s1

InChIKey

IADUWZMNTKHTIN-MLSWMBHTSA-N

Density

1.4±0.1 g/cm3

Solubility

Soluble in DMSO, not in water

Index Of Refraction

1.626

PSA

282.83000

Appearance

Soild powder

Quantity

Milligrams-Grams

Quality Standard

In-house standard

Shelf Life

2 month in rt, long time

Shipping

Room temperature

Storage

Store at -20°C

DM1-SMCC, a potent cytotoxic agent, plays a vital role in the development of antibody-drug conjugates (ADCs) for targeted cancer therapy. Here are four key applications of DM1-SMCC:

Cancer Treatment: At the forefront of targeted cancer therapy, DM1-SMCC is a cornerstone in ADCs engineered to specifically seek out cancer cells. By binding to antibodies that recognize tumor-associated antigens, this cytotoxic agent is delivered directly to malignant cells, minimizing harm to healthy tissues. This precision targeting not only enhances treatment effectiveness but also reduces systemic side effects, heralding a paradigm shift in cancer care.

Pharmacokinetics Studies: In the realm of pharmacokinetics research, DM1-SMCC is a crucial tool for unraveling the behavior and distribution of ADCs in both preclinical and clinical settings. Understanding the journey of these conjugates in the body—from absorption to elimination—is paramount for optimizing dosing strategies and improving therapeutic results. These studies are instrumental in predicting clinical responses and potential adverse reactions.

Drug Development: Serving as a prototypical payload, DM1-SMCC plays a pivotal role in designing the next generation of ADCs. By manipulating linker chemistry or pairing with diverse monoclonal antibodies, scientists can craft innovative ADCs with enhanced stability, potency, and selectivity. This adaptability is key to tailoring treatments for a spectrum of cancer types.

Mechanism of Action Studies: Delving into the intricate mechanisms of ADCs’ cytotoxic effects on cancer cells, DM1-SMCC empowers researchers to explore cellular uptake, intracellular trafficking, and release within targeted cells. These investigations offer profound insights into how ADCs induce cell death, shedding light on resistance mechanisms and optimizing therapeutic approaches. This deep understanding is pivotal for refining cancer treatment strategies and overcoming therapeutic challenges.

1.Understanding How the Stability of the Thiol-Maleimide Linkage Impacts the Pharmacokinetics of Lysine-Linked Antibody-Maytansinoid Conjugates.

Ponte JF;Sun X;Yoder NC;Fishkin N;Laleau R;Coccia J;Lanieri L;Bogalhas M;Wang L;Wilhelm S;Widdison W;Pinkas J;Keating TA;Chari R;Erickson HK;Lambert JM Bioconjug Chem. 2016 Jul 20;27(7):1588-98. doi: 10.1021/acs.bioconjchem.6b00117. Epub 2016 Jun 20.

Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC than for total antibody. Cytotoxic agent release in plasma has been reported with nonmaytansinoid, cysteine-linked ADCs via thiol-maleimide exchange, for example, brentuximab vedotin. For Ab-SMCC-DM1 ADCs, however, the main catabolite reported is lysine-SMCC-DM1, the expected product of intracellular antibody proteolysis. To understand these observations better, we conducted a series of studies to examine the stability of the thiol-maleimide linkage, utilizing the EGFR-targeting conjugate, J2898A-SMCC-DM1, and comparing it with a control ADC made with a noncleavable linker that lacked a thiol-maleimide adduct (J2898A-(CH2)3-DM). We employed radiolabeled ADCs to directly measure both the antibody and the ADC components in plasma.

2.Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.

Ogitani Y;Hagihara K;Oitate M;Naito H;Agatsuma T Cancer Sci. 2016 Jul;107(7):1039-46. doi: 10.1111/cas.12966. Epub 2016 Jun 22.

Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not.

3.A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies.

Deckert J;Park PU;Chicklas S;Yi Y;Li M;Lai KC;Mayo MF;Carrigan CN;Erickson HK;Pinkas J;Lutz RJ;Chittenden T;Lambert JM Blood. 2013 Nov 14;122(20):3500-10. doi: 10.1182/blood-2013-05-505685. Epub 2013 Sep 3.

CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest after internalization and lysosomal processing to lysine-N(ε)-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in severe combined immunodeficient mice with comparable or better activity than rituximab, a combination of cyclophosphamide, vincristine, and prednisone, or bendamustine.

LCMS

Catalog	Product Name	CAS
BADC-01450	MCC-DM1	1100692-14-5
BADC-00574	Lys-SMCC-DM1	1281816-04-3
BADC-00848	MC-DM1	1375089-56-7
BADC-00020	DM1-SMe	138148-68-2
BADC-00601	Mal-VC-PAB-DM1	1464051-44-2
BADC-00668	SC-VC-PAB-DM1	2259318-47-1
BADC-00010	DM1-SPP	452072-20-7
BADC-01378	S-methyl DM1	912569-84-7
BADC-01407	SPDB-DM1
BADC-01411	MPB-VC-PAB-DM1

What is DM1-SMCC?

DM1-SMCC is an ADC linker-payload that combines the payload DM1 with the linker SMCC. DM1 is a maytansinoid, a potent cytotoxic agent, and SMCC (Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate) is a non-cleavable maleimide-based linker. This construct is used to create stable ADCs for targeted drug delivery.

17/2/2018

Dear team, how does the SMCC linker function in ADCs?

The SMCC linker provides a stable covalent connection between the DM1 payload and the antibody. It contains a maleimide group that reacts with the sulfhydryl groups of reduced cysteine residues on the antibody, and an N-hydroxysuccinimide (NHS) ester that forms an amide bond with the DM1 payload. This non-cleavable linker is designed to ensure the ADC remains intact in circulation.

10/11/2022

We are interested in understanding the mechanism of action of the DM1 payload.

The DM1 payload is a derivative of maytansine. It is a tubulin inhibitor that disrupts microtubule dynamics within cancer cells, leading to mitotic arrest and subsequent apoptosis. Its mechanism of action is crucial for its potent antimitotic activity, making it an effective payload for targeted cancer therapy.

3/3/2021

Could you kindly explain why the non-cleavable SMCC linker is important?

The non-cleavable nature of the SMCC linker is a key feature. By forming a highly stable thioether bond with the antibody, it prevents the premature release of the cytotoxic DM1 payload in the bloodstream. This characteristic minimizes off-target toxicity and ensures the payload is delivered specifically to the tumor cells, where it can be released and exert its effect.

24/9/2022

Good morning! What is the difference between DM1 and other maytansinoids?

DM1 is a derivative of maytansine. It has been modified to include a disulfide bond that allows for its conjugation to antibodies. Unlike some other maytansinoids, DM1 is designed for use with specific linkers like SMCC, making it a stable and effective component in ADCs with a proven track record.

16/11/2016

— Dr. Richard Evans, Senior Scientist (USA)

DM1-SMCC purity exceeded our expectations, which is critical for reliable ADC conjugation.

3/3/2021

— Dr. Victoria Brown, ADC Chemist (UK)

We found the delivery speed of DM1-SMCC particularly helpful for urgent preclinical studies.

16/11/2016

— Dr. Stefan Weber, Medicinal Chemist (Germany)

Detailed technical notes on DM1-SMCC allowed our team to optimize linker-toxin ratios efficiently.

24/9/2022

— Dr. Emily Grant, Biochemist (Canada)

Consistent batch performance of DM1-SMCC reduced experimental variability across replicates.