Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody–drug conjugates

Giddens, Anna C.; Lee, Ho H.; Miller, Christian K.; Guo, Jun; Phillips, Gail D. Lewis; Pillow, Thomas H.; Tercel, Moana

doi:10.1016/j.bmc.2016.09.068

Cited by 17 publications

(18 citation statements)

References 25 publications

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“…Although we were unable to test MGC018 in this context due to its lack of cross-reactivity with mouse B7-H3, duocarmycin is a DNA damaging agent that is cytotoxic toward both dividing and non-dividing tumor cells and would be anticipated to be cytotoxic toward both tumor epithelium and tumor-associated vasculature. Furthermore, duocarmycin is also a poor substrate for Pglycoprotein (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…B7-H3 is expressed heterogeneously within the tumor epithelium of solid cancers, and is also expressed by tumor-associated vasculature (21,26) and cancer stem-like cells (27), therefore a linker payload that possessed bystander killing activity and the ability to kill slow-or non-dividing cells was desired. The valine-citrulline-seco duocarmycin hydroxybenzamide-azaindole (vc-seco-DUBA) linker payload was selected because (1) the protease cleavable peptide linker enables bystander killing of B7-H3 negative tumor cells present in heterogeneous solid tumors, and (2) the DNA alkylation activity of the duocarmycin payload can kill both dividing and non-dividing cells, and is resistant to multidrug resistance mechanisms (28)(29)(30)(31). The vc-seco-DUBA linker-payload was conjugated to MGA017 following partial reduction of the interchain disulfide bonds to generate the MGC018 ADC with an average drug-to-antibody-ratio (DAR) of ~2.7 (24).…”

Section: Selection and Generation Of Mgc018mentioning

confidence: 99%

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Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

Scribner

Brown

Son

et al. 2020

Molecular Cancer Therapeutics

104

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B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer and breast cancer. Over-expression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibodydrug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linkerduocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vcseco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa monoclonal antibody through reduced interchain disulfides, with an average drug-to-antibody ratio of ~2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when co-cultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian and lung cancer, as well as melanoma. Additionally, antitumor activity was observed toward patientderived xenograft models of breast, prostate and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Selection and Generation Of Mgc018mentioning

confidence: 99%

Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

Scribner

Brown

Son

et al. 2020

Molecular Cancer Therapeutics

104

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“…Thus, its slow free drug release allows the safe and efficacious administration of much higher doses than the parent-alkylating agent. Tercel et al recently developed two new sets of DNA monoalkylating agents 127 , 128 (CBI–CBI dimer) and 129 , 130 [CBI–pyrrolobenzodiazepine (PBD) dimer], with phenol-CBI and amino-CBI residues and their cytotoxicity against nine human tumor cell lines were tested [ 207 ]. Interestingly, 128 and 130 , amino-CBI analogs found to be less cytotoxic (2- to 190-fold reduction in potency depending on the particular compound and cell line) in comparison to their phenol analogs 127 and 129 ( Fig.…”

Section: Reviewmentioning

confidence: 99%

An overview of recent advances in duplex DNA recognition by small molecules

Bhaduri

Ranjan

Arya

2018

Beilstein J. Org. Chem.

111

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As the carrier of genetic information, the DNA double helix interacts with many natural ligands during the cell cycle, and is amenable to such intervention in diseases such as cancer biogenesis. Proteins bind DNA in a site-specific manner, not only distinguishing between the geometry of the major and minor grooves, but also by making close contacts with individual bases within the local helix architecture. Over the last four decades, much research has been reported on the development of small non-natural ligands as therapeutics to either block, or in some cases, mimic a DNA–protein interaction of interest. This review presents the latest findings in the pursuit of novel synthetic DNA binders. This article provides recent coverage of major strategies (such as groove recognition, intercalation and cross-linking) adopted in the duplex DNA recognition by small molecules, with an emphasis on major works of the past few years.

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“…10 One of the most compelling reasons to investigate tubulysins is that they are not effluxed by Pgp 11 unlike MMAE and some maytansinoids. 12 This lack of efflux gives tubulysin the potential to be effective against multidrugresistant (MDR) cancers. Unfortunately, the high potency was coupled with systemic toxicity and prevented a tubulysin from advancing as a standalone agent.…”

mentioning

confidence: 99%

“…30 We therefore aimed to replace the acetate and modify the amide of tubulysin M (2) to generate tubulysin Pr (9) (Figure 3). Preparation of 9 required an 11-step synthesis (Figure S4), and step 7 required an amide coupling involving a now increasingly sterically hindered amine (12) with a hindered acid chloride 13 (Scheme 1). The resulting amide was only obtained in a 5% yield and necessitated a new synthetic route.…”

mentioning

confidence: 99%

Stabilizing a Tubulysin Antibody–Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors

Staben¹,

Yu²,

Chen

et al. 2017

ACS Med. Chem. Lett.

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The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody-drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent . However, we observed metabolism of a critical acetate ester of the drug, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

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Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody–drug conjugates

Cited by 17 publications

References 25 publications

Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

An overview of recent advances in duplex DNA recognition by small molecules

Stabilizing a Tubulysin Antibody–Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors

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