Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.

DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.

Introduction: There is a high rate of deliveries in adolescents in Mexico. This age group is vulnerable to obstetric complications, including lacerations of the anal sphincter. Objective: To determine the prevalence of third and fourth degree perineal tears in adolescents during childbirth, and to evaluate risk factors in comparison with deliveries with lacerations of adult women. Methods: All obstetric care episodes were reviewed from a public tertiary hospital data in Monterrey, Mexico in 2014. Age, primiparity, delivery instrumentation, episiotomy, body mass index, product weight and tear´s degree were documented at the deliveries with tears of third and fourth degree. Results: The prevalence of third and fourth degree tears of 2.0% was found in the general population, being adolescents the most affected with 2.5%. The unadjusted odds ratio of high-grade tears in adolescent females at delivery, compared to adult females, was 1.36 (95% CI = 0.99-1.86, p= 0.05). No difference was found when comparing risk factors among high-grade tear deliveries in adolescents versus adults. Conclusions: A higher prevalence than previous reported for high grade tears during delivery was found. The data suggest adolescence as a risk factor for high-grade tears during delivery.

Many parents have a misperception of their children's body size; in general, they underestimate overweight and obesity. To identify the difference between parents' perception of their children's nutritional status and measured body mass index. To identify the difference between parents' perception of their children's nutritional status and measured body mass index. A total of 605 children and their parents were assessed. Seventy-four (12.2%) were overweight and 87 were obese (14.3%). There were 161 overweight or obese children, but 98.8% (159) of parents underestimated their children's nutritional status. Parents' underperception of their children's body size accounted for an OR= 2.1 ± 0.5, p= 0.002 (95% confidence interval [CI]: 1.32-3.32) for obesity and an OR = 4.42 ± 1.2, p < 0.001 (95% CI: 2.631-7.439) for overweight. Among parents of overweight and obese children, 98.8% (159) underestimated their children's weight status. Such underestimation by parents may be a significant risk factor for the development and/or persistence of overweight and obesity in their children.