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Global Translational Medicine Role of HTS in cancer therapeutics

These approaches, however, have yet to be harmonized its success in treating chronic myeloid leukemia, it has
with HTS of compound library exceeding 100,000 also shown benefits in steroid-refractory chronic graft-
small molecules. As a result, other advanced techniques versus-host disease due to its activity against PDGFR
are entailed in the HTS to improve the efficiency of action. However, resistance issues have emerged involving
label-free methods using spectroscopic techniques, both Bcr‑Abl‑dependent and ‑independent mechanisms.
such as label-free matrix-assisted laser desorption/ Consequently, new drugs, including dasatinib, nilotinib,
ionization time‑of‑flight (MALDI‑TOF) 49,50 and affinity bosutinib, and ponatinib, have been developed. 55
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mass spectrometry (MS), to measure in vitro target Apart from FDA-approved drugs, several ongoing
engagement of small-molecule ligands. A study by Simon studies have identified active compounds that are still
et al. has demonstrated how using affinity selection under preclinical or clinical trials. For example, a natural
(AS)-based sample preparation can be combined with anticancer compound, cryptotanshinone, is an abietane
MALDI‑TOF to identify orthosteric and allosteric diterpenoid that functions as an anticancer agent by
ligands for protein tyrosine phosphatase 1B (PTP1B). In inhibiting cell proliferation through dual inhibition of
this study, they screened more than 23,000 compounds pSTAT5 and pSTAT3. This dual inhibition effectively
within 24 h, showing its high compatibility with HTS blocks IL‑6‑mediated STAT3 activation and reverses
platform. This method helps to identify multivalent Bcr‑Abl kinase‑independent drug resistance in chronic
ligands for targeted protein degradation, for example, myelogenous leukemia (CML). It has been found that
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proteolysis‑targeting chimeras (PROTACs). Application triple‑negative breast cancer irrespective of BRCA status
of AS-MS helps in minimizing the requirement of can be treated with MLN4924, a selective inhibitor of
purification of a stabilized form of the protein target, neddylation enzyme called NEDD8 activation enzyme
which poses a great challenge for membrane receptor (NAE1), which targets the neddylation pathway and
targets. Another study has shown the importance of promotes G2‑M arrest and apoptosis in CML cells. 57,58
affinity MS in screening 20,000 compounds in one pool
for a GPCR target. This method provides quantitative 2.1. Challenges to target-based screening
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measurement of compound binding to the receptor in Target-based drug discovery is mainly focused on defined
both the conditions where receptor is either purified or drug targets such as a gene, a gene product, or a molecular
embedded in cell membranes. This approach resulted mechanism that have been identified through genetic
in the discovery of three new antagonists of the A analysis or biological studies. In this case, the starting
2A
adenosine receptor, that is, adenosine, UK-432,097, and point is a gene product for which small molecule libraries
NECA (5’‑N‑ethylcarboxamide adenosine). are screened that can modulate its expression, function,
Following this robust screening, final lead compounds or activity. The main drawback to this strategy is the
are evaluated for their pharmacokinetic properties and uncertainty about the occupancy of the molecular drug
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cellular activity of the protein/enzyme. Usually, target- target translation to the desired safe clinical outcome.
based screening assays are straightforward and exhibit In general, this strategy is very straightforward and
less variation due to the homogeneous nature of reactions simple, with several well-defined and tractable technical
with purified proteins. However, it is crucial to note that milestones. These limitations may be attributed to an
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the activity of selected compounds in a cellular context oversimplified assay using recombinant cell lines that
or in vivo does not always mirror their performance in may not precisely reflect the relevant phenotype and fail
these assays. The intracellular environment is highly to translate into the clinical outcome. Another challenge is
complex, with crosstalk between various signaling the engagement of drugs with multiple targets rather than
pathways, potentially leading to undesired or misleading a single target, which can diminish the pharmacological
targets. Factors such as cellular impermeability of the value of the drug and may also cause unusual side effects
compound or compound metabolism can contribute to and dysfunctions.
undesirable toxic effects. In spite of these challenges, Nonetheless, this strategy is lauded as a fast and
most of the successful drugs results from target-based cost-effective process, supported by the easily available
screening offer new therapeutic options that are precise advanced computational tools used to understand how a
and personalized to specific mutations or can counter drug interacts with its target. Virtual drug screening and de
resistance. 53 novo drug design can improve the outcomes of this strategy.
Imatinib, a tyrosine kinase inhibitor, was the pioneering This application can be used to optimize lead compounds
cancer therapy that demonstrated targeted specificity by structural modifications to enhance activity or decrease
against BCR‑ABL, c‑KIT, and PDGFRA proteins. Beyond or eliminate adverse side effects. 60
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Volume 3 Issue 1 (2024) 6 https://doi.org/10.36922/gtm.2448