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Drug Discovery Today Aug 2021Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the... (Review)
Review
Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody-drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.
Topics: Animals; Antineoplastic Agents; Drug Development; Drug Evaluation, Preclinical; Duocarmycins; Humans; Immunoconjugates; Neoplasms
PubMed: 34224904
DOI: 10.1016/j.drudis.2021.06.012 -
Molecules (Basel, Switzerland) Jun 2021Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein....
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA-TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Female; Humans; Indole Alkaloids; Maleates; Mice; Mice, Inbred BALB C; Micelles; Nanoparticles; Polystyrenes; Triple Negative Breast Neoplasms
PubMed: 34207832
DOI: 10.3390/molecules26123532 -
Molecular Cancer Therapeutics Jun 2023MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor, which is widely overexpressed in various solid cancer types, is an attractive target for...
MET, the cell-surface receptor for the hepatocyte growth factor/scatter factor, which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. BYON3521 is a novel site-specifically conjugated duocarmycin-based antibody-drug conjugate (ADC), comprising a humanized cysteine-engineered IgG1 monoclonal antibody with low pmol/L binding affinity towards both human and cynomolgus MET. In vitro studies showed that BYON3521 internalizes efficiently upon MET binding and induces both target- and bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high MET-expressing cancer cell lines; in moderate and low MET-expressing cancer cell lines good potencies and partial efficacy were observed. In mouse xenograft models, BYON3521 showed significant antitumor activity upon single-dose administration in multiple non-MET-amplified tumor types with low, moderate, and high MET expression, including complete tumor remissions in models with moderate MET expression. In the repeat-dose Good Laboratory Practice (GLP) safety assessment in cynomolgus monkeys, BYON3521 was well tolerated and based on the observed toxicities and their reversibility, the highest non-severely toxic dose was set at 15 mg/kg. A human pharmacokinetics (PK) model was derived from the PK data from the cynomolgus safety assessments, and the minimal efficacious dose in humans is estimated to be in the range of 3 to 4 mg/kg. In all, our nonclinical data suggests that BYON3521 is a safe ADC with potential for clinical benefit in patients. A first-in-human dose-escalation study is currently ongoing to determine the maximum tolerated dose and recommended dose for expansion (NCT05323045).
Topics: Animals; Humans; Mice; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Immunoconjugates; Immunoglobulin G; Xenograft Model Antitumor Assays
PubMed: 37042205
DOI: 10.1158/1535-7163.MCT-22-0596 -
ACS Central Science Apr 2023Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs...
Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to -Duocarmycins Targeting the Thioredoxin System.
Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) system. The Trx system is a critical cellular redox axis that is tightly linked to dysregulated redox/metabolic states in cancer, yet it cannot be addressed by current bioreductive prodrugs, which mainly cluster around oxidized nitrogen species. We instead harnessed Trx/TrxR-specific artificial dichalcogenides to gate the bioactivity of 10 "off-to-on" reduction-activated duocarmycin prodrugs. The prodrugs were tested for cell-free and cellular reductase-dependent activity in 177 cell lines, establishing broad trends for redox-based cellular bioactivity of the dichalcogenides. They were well tolerated in mice, indicating low systemic release of their duocarmycin cargo, and anti-tumor efficacy trials in mouse models of breast and pancreatic cancer gave promising indications of effective tumoral drug release, presumably by bioreductive activation. This work therefore presents a chemically novel class of bioreductive prodrugs against a previously unaddressed reductase chemotype, validates its ability to access -compatible small-molecule prodrugs even of potently cumulative toxins, and so introduces carefully tuned dichalcogenides as a platform strategy for specific bioreduction-based release.
PubMed: 37122469
DOI: 10.1021/acscentsci.2c01465 -
Pharmaceutics Apr 2021HER-3 is becoming an attractive target for antibody-drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several...
HER-3 is becoming an attractive target for antibody-drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.
PubMed: 33918158
DOI: 10.3390/pharmaceutics13040483 -
Nature Communications Nov 2021Microbes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the...
Microbes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the spirocyclopropylcyclohexadienone (SCPCHD) family, which includes the duocarmycins, CC-1065, gilvusmycin, and yatakemycin. The yatakemycin biosynthesis cluster in Streptomyces sp. TP-A0356 contains an AlkD-related DNA glycosylase, YtkR2, that serves as a self-resistance mechanism against yatakemycin toxicity. We previously reported that AlkD, which is not present in an SCPCHD producer, provides only limited resistance against yatakemycin. We now show that YtkR2 and C10R5, a previously uncharacterized homolog found in the CC-1065 biosynthetic gene cluster of Streptomyces zelensis, confer far greater resistance against their respective SCPCHD natural products. We identify a structural basis for substrate specificity across gene clusters and show a correlation between in vivo resistance and in vitro enzymatic activity indicating that reduced product affinity-not enhanced substrate recognition-is the evolutionary outcome of selective pressure to provide self-resistance against yatakemycin and CC-1065.
Topics: Anti-Bacterial Agents; Bacterial Proteins; DNA Damage; DNA Glycosylases; DNA Repair; Duocarmycins; Multigene Family; Mutagens; Streptomyces
PubMed: 34836957
DOI: 10.1038/s41467-021-27284-7 -
Yakugaku Zasshi : Journal of the... 2022Among my recent work on the syntheses of complex natural products based on the development of a novel synthetic method for the heteroaromatic skeleton, this article... (Review)
Review
Among my recent work on the syntheses of complex natural products based on the development of a novel synthetic method for the heteroaromatic skeleton, this article primarily deals with the total syntheses of (+)-CC-1065, isobatzeline A/B, and batzeline A. These syntheses were accomplished via a novel indole synthesis utilizing a ring expansion reaction of benzocyclobutenone oxime sulfonate as the key step. The 1,2-dihydro-3H-pyrrolo[3,2-e]indole segments of (+)-CC-1065 were rapidly constructed via a two-directional double-ring expansion strategy. Highly substituted pyrrolidine-fused common 5-chloro-2-methylthioindoles of isobatzeline A/B and batzeline A were constructed using a ring expansion reaction of benzocyclobutenone oxime sulfonate with NaSMe and a benzyne-mediated cyclization/functionalization reaction.
Topics: Biological Products; Chemistry, Organic; Cyclization; Duocarmycins; Indoles; Oximes; Pyrroloiminoquinones; Quinolones
PubMed: 35110456
DOI: 10.1248/yakushi.21-00199 -
JACS Au May 2023[This corrects the article DOI: 10.1021/jacsau.2c00448.].
[This corrects the article DOI: 10.1021/jacsau.2c00448.].
PubMed: 37234106
DOI: 10.1021/jacsau.3c00137 -
Biomedicines Mar 2021Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great... (Review)
Review
Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great challenge. The cytochrome P450 (CYP) family of enzymes contribute to cancer cell proliferation, cell signaling and drug metabolism with implications for treatment outcomes. A clearer understanding of CYP expression is important in the pathogenesis of breast cancer as several isoforms play critical roles in metabolising steroid hormones and xenobiotics that contribute to the genesis of breast cancer. The purpose of this review is to provide an update on how the presence of CYPs impacts on standard of care (SoC) drugs used to treat breast cancer as well as discuss opportunities to exploit CYP expression for therapeutic intervention. Finally, we provide our thoughts on future work in CYP research with the aim of supporting ongoing efforts to develop drugs with improved therapeutic index for patient benefit.
PubMed: 33809117
DOI: 10.3390/biomedicines9030290 -
Cell Chemical Biology May 2022We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I,...
We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I, is a precursor of the anticancer duocarmycin family that preserves the class's sequence-specific DNA binding but lacks its signature DNA alkylating cyclopropyl warhead. While less active than duocarmycin, PDE-I retains comparable antimalarial potency to chloroquine. Importantly, PDE-I is >1,000-fold less toxic to human cell lines than duocarmycin, with mitigated impacts on eukaryotic chromosome stability. PDE-I treatment induces severe defects in parasite nuclear segregation leading to impaired daughter cell formation during schizogony. Time-of-addition studies implicate parasite DNA metabolism as the target of PDE-I, with defects observed in DNA replication and chromosome integrity. We find the effect of duocarmycin and PDE-I on parasites is phenotypically indistinguishable, indicating that the DNA binding specificity of duocarmycins is sufficient and the genotoxic cyclopropyl warhead is dispensable for the parasite-specific selectivity of this compound class.
Topics: Animals; Antimalarials; Biological Products; DNA; Duocarmycins; Folic Acid Antagonists; Humans; Malaria; Parasites
PubMed: 34710358
DOI: 10.1016/j.chembiol.2021.10.005