Structure of CC-1065 (NSC-298223), a new antitumor antibiotic.

Martin, David G.; Chidester, C. G.; Duchamp, D. J.; Mizsak, S. A.

doi:10.7164/antibiotics.33.902

Cited by 95 publications

(36 citation statements)

References 3 publications

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“…Duocarmycins and CC-1065 are natural products that were first isolated from Streptomyces bacteria in the late 70s (10). This class of compounds binds to the minor groove in DNA and subsequently alkylates specific adenine residues via ring opening of their cyclopropyl group, which eventually leads to cell death (11).…”

Section: Design and Preparation Of Syd983mentioning

confidence: 99%

“…A new-generation platform of LDs has been developed on the basis of chemically synthesized duocarmycins which are DNA-alkylating cytotoxic drugs (10,11) that induce cell death in both dividing and nondividing cells. The aim is to improve the currently used LDs and increase the TI that can be obtained with ADCs based on these new LDs as compared with that of the earlier generation ADCs.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Dokter

Ubink

Lee

et al. 2014

Molecular Cancer Therapeutics

140

125

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A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody-drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology. Mol Cancer Ther; 13(11); 2618-29. Ó2014 AACR.

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Section: Design and Preparation Of Syd983mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Dokter

Ubink

Lee

et al. 2014

Molecular Cancer Therapeutics

140

125

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show abstract

“…11) (along with more recent duocarmycin derivatives) is among the most potent antitumor agents discovered to date [86][87][88][89][90][91]. Strictly speaking, CC-1065 is not a QM, but the cyclopropane moiety present on its structure is, from a reactivity point of view, a bioisosteric form of the methide found in QMs.…”

Section: Modulation Of Qm Reactivity Towards Nuc-leophiles Drugs Withmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…These new DNA-binding subunits will be used for the synthesis of new prodrug analogues of the antibiotic CC-1065 to overcome the problem of poor water solubility during biological testing within the ADEPT approach. Furthermore, (1-methylpiperidin-4-yl)methanol (16), which is a valuable building block of pharmaceutical interest, has been prepared from ethyl isonipecotate (14) in 84 % yield over two steps.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of New Water‐Soluble DNA‐Binding Subunits for Analogues of the Cytotoxic Antibiotic CC‐1065 and Their Prodrugs

Tietze

Major

2006

Eur J Org Chem

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Structure of CC-1065 (NSC-298223), a new antitumor antibiotic.

Cited by 95 publications

References 3 publications

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Synthesis of New Water‐Soluble DNA‐Binding Subunits for Analogues of the Cytotoxic Antibiotic CC‐1065 and Their Prodrugs

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