Duocarmycins

Creative Biolabs offers customarily prepared high quality antibody-drug conjugates (ADCs) using duocarmycin and duocarmycin analogs as payloads for targeted anti-cancer therapies and a variety of other applications.

Duocarmycin mode of action (MOA)
Duocarmycins are a series of natural products originally isolated from Streptomyces bacteria in 1988. They exhibit an impressively high cytotoxicity and are subsequently developed into anti-tumor agents. Duocarmycin analogues, among which CC-1065 and duocarmycin SA are the most widely used, represent a series of extremely powerful antineoplastic compounds that display high cytotoxicity against the growing cancer cells in culture. Duocarmycin analogues are DNA minor groove binding agents that also exert adenine-N3 alkylation activity and an AT-sequence selectivity. In terms of mode of action, duocarmycin analogues bind the minor groove of DNA and then induce irreversible DNA alkylation that hinders DNA architecture and structural integrity. The alkylation of DNA eventually leads to DNA cleavage and subsequently, tumor cell death via apoptosis. Duocarmycins are capable of applying this MOA at any phase in the cellular cycle and they are believed to have better anti-tumor activities comparing to tubulin binders, which only attack tumor cells during the mitotic state. What’s more, duocarmycin analogues have also been demonstrated to be effective on solid tumors.

Two duocarmycin analogs: CC-1065 and duocarmycin SA with highlighted pharmacological active units (Toxins, 2009). Rightmost: a model representing the binding of duocarmycin analogs to DNA minor groove (the payload is shown in red, PNAS, 1996). Both CC-1065 and duocarmycin SA have been shown to be active against various tumor types in vivo and a broad spectrum of human tumor cell lines in vitro.

Synthetic Analogs of Duocarmycin
Adozelesin, bizelesin and carzelesin are artificially synthesized analogs of duocarmycins and are members of the cyclopropylpyrroloindole family. These drugs have high research and clinical values and all of them have advanced into clinical trials for cancer treatments. Adozelesin is an alkylating small groove DNA binder which quickly restrains DNA replication in treated cells via a trans-acting mechanism. Adozelesin primarily arrests cells in S phase. Bizelesin targets the small groove of DNA and causes DNA cross-linking, thereby restraining DNA replication and RNA synthesis. It also strengthens p21 and p53 induction and induces G2/M cell-cycle arrest, leading to slow cell death but without apoptosis. Carzelesin is a cyclopropylpyrroloindole prodrug containing a nonreactive chloromethyl forebody that is functional upon activation. It is activated by hydrolysis of the phenylurethane substituent to generate U-76073 and a subsequent ring closure step yields the cyclopropyl-containing U-76074 form that is active in DNA binding.

Generation of the active U-76074 from Carzelesin activation (Cancer Res, 1992).

Duocarmycins-based ADCs
Duocarmycin analogs are effective in the picomolar range. They are excellent candidates as payloads that yield ADCs with maximized cell-killing potency for regular and more importantly, multi-drug resistant cancer cells. A linker-drug platform containing a cleavable linker and a duocarmycin analog, DUBA (final active drug form), has been reported and developed into several new-generation ADCs for in vitro or in vivo efficacy evaluations. SYD983, a HER2-targeting ADC based on trastuzumab, is a leading ADC derived from this platform. SYD983 results in decreased tumor growth in a BT-474 mouse xenograft in vivo and is stable in human and cynomolgus monkey plasma.

Mechanism of activation of SYD983/SYD985 inside the tumor cell to release the toxic form of duocarmycin. YD983 is comprised of trastuzumab conjugated with vc-seco-DUBA through Cys thiol groups. Upon internalization, the linker is first cleaved in the lysosome by proteases such as cathepsin B followed by two continuous self-elimination reactions to generate seco-DUBA, which undergoes spontaneous rearrangement to yield the active duocarmycin drug form, DUBA, which binds and alkylates DNA (Mol Cancer Ther, 2014).

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help you develop duocarmycin-linker complexes using readily available or customized linkers for antibody conjugation in a timely and cost-effective manner. Our customarily tailored services and high quality products will contribute greatly to the success of your projects.

Creative Biolabs also provides other various services regarding ADC development. Please feel free to contact us for more information and a detailed quote.

References:

1. Tietze, L.F.; et al. Determination of the biological activity and structure activity relationships of drugs based on the highly cytotoxic duocarmycins and CC-1065. Toxins. 2009, 1(2): 134-150.
2. Dokter, W.; et al. Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther. 2014, 13(11): 2618-2629.
3. Li, L. H.; et al. Cytotoxicity and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue. Cancer Res. 1992, 52: 4904-4913.
4. Sugiyama, H.; et al. Distamycin A modulates the sequence specificity of DNA alkylation by duocarmycin A. PNAS. 1996, 93(25): 14405–14410.