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Global Translational Medicine Role of HTS in cancer therapeutics

catenin complexes in vitro, inhibition of colon cancer gain of secondary target mutations, gene amplification,
cell proliferation, β-catenin-regulated transcription, and and compensatory activation of prosurvival signaling
β-catenin-mediated axis duplication in Xenopus embryos. pathways. A recent study by Liu et al. has shown that the
Another study by Yu et al. highlighted the special resistance to a MEK inhibitor trametinib can be overcome
AT‑rich binding protein‑2 (SATB2)/β‑catenin/TCF‑LEF through epigenetic reprogramming using histone
pathway in transformation and carcinogenesis. SATB2 deacetylase (HDAC) inhibitors, for example, trichostatin
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is a transcription factor and epigenetic regulator that A (TSA), suberoylanilide hydroxamic acid (SAHA),
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is mostly overexpressed in colorectal cancer. Silencing LBH589, and PXD101 in advanced ovarian cancer. The
of SATB2 inhibits TCF/LEF activity and its targets. novelty of this study lies in the establishment of a series of
Hence, these studies suggest a critical role of Wnt patient-derived advanced ovarian cancer models that were
signaling pathway in cancer development, and targeting sensitive or resistant to trametinib. This model illustrated
this pathway, in combination with current available that enhancer reprogramming led to sustained activation
chemotherapies, might be beneficial for controlling the of the MAPK pathway, which plays a crucial role in MEK
cancer. inhibitor resistance. They also performed combinatorial
Another important signaling pathway is EGFR drug screening with a customized epigenetics compound
signaling that controls cellular and molecular pathways, library from Selleck Chemicals in A2780‑R and
and any alterations to this signaling can lead to SKOV3 cells. LBH589 (Panobinostat, HDAC inhibitor)
carcinogenesis. This receptor tyrosine kinase belongs the in combination with trametinib maximizes the clinical
ERBB family of receptors, and its activation regulates benefit. They found that the combinatorial treatment
KRAS and PI3K/PTEN pathways. Torrance et al. retarded tumor growth in the SKOV3 xenograft model.
identified triphenyl tetrazolium (TPT) and a sulfinyl- These findings demonstrated that HDAC inhibitors
to‑cytidine derivative (SC‑D) as novel KRAS pathways overcome resistance through the suppression of ERK
inhibitors in DLD‑1 colorectal cancer cells in which restoration.
key tumorigenic genes had been deleted by targeted IFNs such as IFN-α and IFN-β play a key role in
homologous recombination and yellow fluorescent cancer and several chronic diseases after binding to their
protein were expressed, while a blue fluorescent protein respective receptors, IFNAR1 and IFNAR2. This receptor
expression vector was introduced into an isogenic complex activates Janus-activated kinases (JAKs) and
derivative (lines (HCT116/HKH) in which the mutant signal transducers and activators of transcription (STAT)
K-Ras allele had been deleted. TPT and SC‑D were pathways. HTS against type-I IFN with the secreted
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identified among 30,000 compounds through large embryonic alkaline phosphatase (SEAP) reporter gene assay
screening, which displayed selective activity in vitro involving 32,000 compounds resulted in 25 confirmed hits.
and inhibited tumor xenografts containing mutant Ras. Further screening by cytotoxicity assay in neuroblastoma
Similarly, another HTS study identified two series of cell line SH‑SY5Y showed two hits (CD2093‑G007 and
substituted 4-anilino-3-quinolinecarbonitriles as potent RUS0903‑C006) that decreased viability to less than 50%.
mitogen-activated protein/extracellular signal-regulated Finally, RUS0910-G009 exhibited inhibition of STAT1 and
kinase 1 (MEK1) inhibitors. These compounds had the STAT3 phosphorylation and suppression of IRF7 mRNA
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same cyanoquinoline cores but differed in their respective transcription. 163
aniline groups. Both classes inhibited in vitro growth of Several investigations were conducted to find DNA
human tumor cell lines while class 2 that is 3-chloro-4- repair factors through HTS assays to screen inhibitors
(1-methylimidazol-2-sulfanyl)aniline inhibited kinase targeting PARP-1, Ape1, RecA, and Rad51. 164-168
activity upstream of Raf and had dual effect on MEK Dillon et al. have notably developed a novel FlashPlate
and MAPK phosphorylation and inhibited growth of the scintillation proximity assay of large compound libraries
human colon tumor cell line LoVo (at 50 and 100 mg/kg for HTS to identify inhibitors of PARP-1. This assay
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BID) in a nude mouse xenograft model). 158 was originally developed for the 96-well FlashPlate, but
MEK inhibitors such as trametinib and selumetinib the authors have transformed it into a 384-well format
have been clinically approved for use in several tumor with sufficient sensitivity to determine accurate IC50
types of cancers such as melanoma, non-small cell values and adaptability for kinetic evaluation of lead
lung cancer, and low-grade serous ovarian cancer. 159-161 molecules. Further, Peterson et al. developed a robust
Despite having promising therapeutic efficacy, these method to screen large number of small molecules
inhibitors showed limited success clinically due to the in HTS against RecA using commercial reagents
®
rapid development of resistance that might be caused by (Transcreener( ) adenosine 5’-O-diphosphate [ADP]

Volume 3 Issue 1 (2024) 11 https://doi.org/10.36922/gtm.2448