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Global Translational Medicine Role of HTS in cancer therapeutics

subfamily members such as Aurora A and Aurora B in small molecules. HTS should be designed very carefully
combination would be ineffective. Instead, each should to determine effective compounds for clinical usage
be treated autonomously due to their distinct biological (Table 2).
responses. 178
Cell cycle is tightly regulated by the p53 gene, which 6. Conclusion
governs the activity of cell cycle kinases such as cyclin- HTS sets experiments on a more rapid mode and
dependent kinases (CDK4/6 and CDK2). Its inactivation is applicable to a broader range of targets without
or mutation causes dysregulation in proliferation and necessitating prior knowledge of target and ligands or
apoptosis, leading to cancer. Therefore, an attempt has phenotypic assays. Challenges confronting the HTS
been made in drug development to restore its activity using practitioners are not only limited to the endpoint readouts
small molecules modulators (CP‑31398, PRIMA1, and or the quality of the biology but also the quality and
Nutlins) in p53-deficient human colon tumor xenografts quantity of compounds being tested. It requires a very
(HCT116/p53 or DLD1). These compounds were able broad knowledge base with expertise involving multiple
179
-/-
to reactivate p53 reporter activity via increasing its targeted areas of biology, chemistry, engineering, information
genes such as p21 (WAF1) and death receptor 5 (DR5). technology, and logistics. All drug discovery strategies
are fraught with pitfalls; therefore, practitioners need
Similarly, heat-shock protein 90 (HSP90) is an to integrate hit identification approaches to maximize
important molecular chaperone, which is overexpressed in success rate. Various drug screening methods in HTS have
patients with cancer. 180,182 HIF-1 pathway is considered to yielded numerous potent compounds currently utilized
be an important signaling pathway that plays a crucial role in treatment procedures. Despite these advancements,
in tumor progression and angiogenesis by upregulating drug selection assays have not fully matured to produce
kinases and hypoxia-inducible factor-1 (HIF-1). 183-185 endpoints directly relevant to the disease phenotype.
Enzymes involved in DNA modification, such as histone This review underscores the importance of selecting
acetyltransferases and histone deacetylases, play a critical appropriate endpoints that closely mimic the desired
role in chromatin modification. These enzymes are phenotype to identify efficacious drugs. While new
essential for post-translational modifications, catalyzing technologies such as genomics and proteomics provide
the acetylation and deacetylation of histones on specific abundant knowledge about targets and their signaling, it
lysine residues. Their possible involvement in the is still necessary to elucidate specific signaling axes that
pathology of conditions like cancer, asthma, and viral lead to the correct clinical outcomes. Thus, continued
infections highlights their significance in understanding exploration is crucial for unearthing innovative anticancer
and potentially targeting these enzymes for therapeutic agents and maximizing patient benefits.
interventions. 186-189
Moreover, a genome-based strategy has successfully Acknowledgments
emphasized the use of herceptin, a humanized antibody None.
targeting the ErbB2 receptor, for the treatment of breast
cancer. This is particularly effective in cases where breast Funding
cancer patients exhibit overexpression of the receptor. None.
190
Another example is farnesyltransferase inhibitor R115777
that showed efficacy in the treatment of human breast Conflict of interest
cancer xenografts and in patients with advanced breast
191
cancer. Hopefully, further understanding of the genetic The authors declare no conflicts of interest.
192
versatility of breast cancer holds the potential to identify Author contribution
more druggable targets for HTS. In addition, compounds,
either used in combination or alone, have demonstrated Conceptualization: Ruchi Roy, Sunil Kumar Singh
superior efficacy and tolerability compared to standard Writing – original draft: Ruchi Roy, Sunil Kumar Singh
endocrine therapy, such as tamoxifen. For instance, the Writing – review and editing: All authors
aromatase inhibitor Arimidex (anastrazole) has shown
promising results in clinical trials for the treatment Ethics approval and consent to participate
of hormone receptor-positive breast cancer in post- Not applicable.
menopausal women. 193,194
These studies collectively suggest that several signaling Consent for publication
pathways can be targeted while selecting multi-target Not applicable.

Volume 3 Issue 1 (2024) 13 https://doi.org/10.36922/gtm.2448