Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of ...suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
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•CD276/B7-H3 is broadly overexpressed in both cancer cells and tumor vasculature•Both angiogenic and non-angiogenic tumor vasculature express CD276•Anti-CD276-drug conjugates display potent anti-tumor and anti-metastatic activity•Pyrrolobenzodiazepine dimers are optimal warheads for targeting tumor vasculature
Seaman et al. show that CD276 is broadly overexpressed in cancer cells and tumor vascular cells and demonstrate anti-CD276-drug conjugates as promising anti-cancer reagents. The drug selected for conjugation is important because tumor vascular cells can be resistant to a drug to which tumor cells are sensitive.
Hepatocellular carcinoma (HCC) accounts for approximately 85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was ...reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase mixed lineage leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin-MLL inhibitor MI-503 shows antitumor activity in
and
models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in
HCC models. When applied
, MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including
, and displaces the menin-MLL1 complex from the
promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin-MLL interaction might represent a promising therapeutic approach for HCC.
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Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their ...interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.
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•MI-503 and MI-463 demonstrate profound on-target activity in MLL leukemia cells•MI-503 and MI-463 show substantial survival benefit in mouse models of MLL leukemia•Menin-MLL inhibitors do not impair normal hematopoiesis in vivo•MI-503 and MI-463 provide molecular scaffold for clinical lead identification
Borkin et al. develop highly potent and orally bioavailable small molecules that block the interaction between menin and MLL. These compounds inhibit the growth of model and patient-derived leukemia cells that express MLL-fusion proteins in vitro and prolong the survival of mice bearing MLL leukemia.
ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors ...is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on ...targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a ...valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein–protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein–protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.
5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely ...1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.
By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole‐, indole‐, and pyrazole‐based compounds were evaluated as potential fructose 1,6‐bisphosphatase ...(FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1‐4‐(trifluoromethyl)benzoyl‐1H‐indole‐5‐carboxamide, 1‐(α‐naphthalen‐1‐ylsulfonyl)‐7‐nitro‐1H‐indole, 5‐(4‐carboxyphenyl)‐3‐phenyl‐1‐3‐(trifluoromethyl)phenyl‐1H‐pyrazole, 1‐(4‐carboxyphenylsulfonyl)‐1H‐pyrrole, and 1‐(4‐carbomethoxyphenylsulfonyl)‐1H‐pyrrole were synthesized and tested for inhibition of FBPase. The IC50 values were determined to be 0.991 and 1.34 μM, and 575, 135, and 32 nM, respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 μM) by an order of magnitude; indeed, the best inhibitor showed an IC50 value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.
Computer‐based drug design was applied to systematically develop second‐generation lead compounds for the improved inhibition of fructose 1,6‐bisphosphatase. The selected compounds were synthesized, and their biological potency was determined by in vitro assays.
A novel method for the preparation of trifluoroacetaldehyde (fluoral, TFAc, CF
3CHO) from commercially available trifluoroacetaldehyde ethylhemiacetal (TFAE) by microwave irradiation is described. ...The isolation, characterization and reaction of fluoral with various nucleophiles are studied to verify the diverse applicability of this new method.
A novel method for the preparation of trifluoroacetaldehyde (fluoral, TFAc, CF
3CHO) from commercially available trifluoroacetaldehyde ethylhemiacetal (TFAE) by microwave irradiation is described. The isolation, characterization and reaction of fluoral with various nucleophiles were studied to verify the diverse applicability of this new method.
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