There is still much work to be done to directly target the STAT3 and STAT5 proteins. As yet, there is still no direct STAT3 inhibitor in the clinic. While the SH2 domain remains a popular target for therapeutic intervention, the DNA-binding domain and N-terminal region are now attracting attention as possible sites for inhibition. Multiple putative STAT3 and STAT5 inhibitors have now been patented across a broad spectrum of chemotypes, each with their own advantages and limitations.
Pharmacologic blockade of STAT3 activation in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) cell lines characterized by kinase-independent resistance re-sensitized CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. Benzoic acid-based STAT3 inhibitors, SH-4-54 and SH-5-07, developed in our lab, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD-1 mice) revealed that both SH-4-54 and SH-5-07 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (SNAr). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in-depth structure activity relationship (SAR) study of the SH-4-54 scaffold was conducted. The studies revealed that AM-1-124, possessing a 2,3,5,6-tetrafluorophenylsulfonamide, retained STAT3 protein affinity (Ki = 15 μM), as well as selectivity over STAT1 (Ki >250 μM). Moreover, in both hepatocytes and in in vivo pharmacokinetic studies (CD-1 mice), AM-1-124 was found to be dramatically more stable than SH-4-54 (t1/2 = 1.42 h cf. 10 minutes, respectively). AM-1-124 represents a promising STAT3-targeting inhibitor with demonstrated bioavailability, suitable for evaluation in preclinical cancer models.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% one-year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a 3D co-culture model, AES-135 kills low passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts (CAFs), and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.
Epigenetic targeting
has emerged as an efficacious therapy for
hematological cancers. The rare and incurable T-cell prolymphocytic
leukemia (T-PLL) is known for its aggressive clinical course. Current
epigenetic agents such as histone deacetylase (HDAC) inhibitors are
increasingly used for targeted therapy. Through a structure–activity
relationship (SAR) study, we developed an HDAC6 inhibitor KT-531,
which exhibited higher potency in T-PLL compared to other hematological
cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity,
on-target biological activity, and a safe therapeutic window in nontransformed
cell lines. In primary T-PLL patient cells, where
HDAC6
was found to be overexpressed, KT-531 exhibited strong biological
responses, and safety in healthy donor samples. Notably, combination
studies in T-PLL patient samples demonstrated KT-531 synergizes with
approved cancer drugs, bendamustine, idasanutlin, and venetoclax.
Our work suggests HDAC inhibition in T-PLL could afford sufficient
therapeutic windows to achieve durable remission either as stand-alone
or in combination with targeted drugs.
The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure−activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (K i = 0.7 nM) and inhibits the enzyme function (IC 50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn 2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn 2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.
PTP1B is a master regulator in the insulin and leptin metabolic pathways. Hyper-activated PTP1B results in insulin resistance and is viewed as a key factor in the onset of type II diabetes and obesity. Moreover, inhibition of PTP1B expression in cancer cells dramatically inhibits cell growth in vitro and in vivo. Herein, we report the computationally guided optimization of a salicylic acid-based PTP1B inhibitor 6, identifying new and more potent bidentate PTP1B inhibitors, such as 20h, which exhibited a > 4-fold improvement in activity. In CHO-IR cells, 20f, 20h, and 20j suppressed PTP1B activity and restored insulin receptor phosphorylation levels. Notably, 20f, which displayed a 5-fold selectivity for PTP1B over the closely related PTPσ protein, showed no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain. Finally, 20i and 20j displayed nanomolar inhibition of PTPσ, representing interesting lead compounds for further investigation.
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