Current Enzyme Inhibition - Volume 16, Issue 1, 2020

Breast cancer, the most common health burden to women globally, is considered a major cause of death for women every year. Many signal transduction pathways can cause breast cancer. The kinase inhibitors can interrupt the signaling pathways, minimize tumor growth and consequently cure the disease. The scientists have discovered many kinase inhibitors as targeted drugs for breast cancer. In recent years, the inhibitors of EGFR, HER2, VEGFR, PI3K, CDK4/6, PARP and hormone receptor have been studied well for curing breast cancer. The FDA has approved a few kinase drugs such as trastuzumab, lapatinib, neratinib, palbociclib, abemaciclib, alpelisib to treat breast cancer recently. In this review, we summarized the latest development of kinase inhibitors as breast cancer therapy.

Enzyme aromatase uses several androgen substrates for the biosynthesis of estrogen, i.e. conversion of androstenedione to estrone and testosterone to biologically potent estradiol. Aromatase inhibitors (AIs) such as anastrozole, letrozole and exemestane have been established in standard endocrine therapy of breast cancer, by interfering with estrogen signaling cascade. Steroid sulphatase (STS) regulates the level of active oestrogens and androgens in human target organs and steroidogenic tissues, which have a key role in hormone dependent breast cancers (HDBC). Sulfatase is still under the exploration stage and is yet to emerge as a potential therapeutic target in breast cancer. The discovery of estrone 3-O-sulfamate (EMATE), a highly potent irreversible STS inhibitor, accelerated the development of potent steroidal and nonsteroidal STS inhibitors. Attempts are also being made for the development of dual inhibitors of AI and STS, as an alternative approach to overcome the acquired resistance. This review includes the molecular structures and biochemistry of aromatase and sulphatase enzymes. The advances in the development of inhibitors of the two enzymes have also been outlined.

Breast cancer is the most prevalent type of cancer and one of the leading causes of death among all the cancers affecting women worldwide. Preliminary cause of development of tumors in the breast cancer in post-menopausal women is mostly the increased estrogen levels in the body which could be the result of overexpression of aromatase CYP450 i.e. CYP19A1. Aromatase is the only enzyme present in humans that brings about aromatization of A-ring of 19-carbon androgens to form 18-carbon estrogens. Inhibiting aromatase enzyme thereby decreasing the estrogen levels in the postmenopausal women has been considered as an important strategy for the management of breast cancer. Three generations of aromatase inhibitors including steroidal viz. testolactone, formestane, exemestane and non-steroidal viz. aminoglutethimide, fadrozole, letrozole, anastrozole, the two classes of drugs have been approved for clinical use for the treatment of breast cancer. A large number of research and review articles have been reported so far describing the therapeutic efficacy of steroidal and non-steroidal aromatase inhibitors. However, steroidal aromatase inhibitors, being more selective inhibitors and having certain other advantages, overruled the discovery of novel aromatase inhibitors compared to the non-steroidal aromatase inhibitors which lack selectivity for CYP450 aromatase. In this review, efforts have been made to describe the developments of steroidal aromatase inhibitors to date.

Prostate cancer has become a global health concern as it is one of the leading causes of mortality in males. With the emerging drug resistance to conventional therapies, it is imperative to unravel new molecular targets for disease prevention. Cytochrome P450 (P450s or CYPs) represents a unique class of mixed-function oxidases which catalyses a wide array of biosynthetic and metabolic functions including steroidogenesis and cholesterol metabolism. Several studies have reported the overexpression of the genes encoding CYPs in prostate cancer cells and how they can be used as molecular targets for drug discovery. But due to functional redundancy and overlapping expression of CYPs in several other metabolic pathways there are several impediments in the clinical efficacy of the novel drugs reported till now. Here we review the most crucial P450 enzymes which are involved in prostate cancer and how they can be used as molecular targets for drug discovery along with the clinical limitations of the currently existing CYP inhibitors.

Prostate cancer is one of the prominent death cause in males with alarming rates of inclusion of new cases each year. There are many new classes of anti-tumor agents already investigated that modulate the epigenetic or non-epigenetic mechanisms such as cell cycle arrest, apoptosis, cell death within cancer cells. Histone deacetylase (HDAC) inhibitors are one of them. In recent times, the use of HADC inhibitors are approved as a clinical molecule to treat a group of malignancies. Vorinostat and depsipeptide are two new HDAC inhibitors that are approved by the Food and Drug Administration. The present review is an effort to summarize the recent findings related to HDAC inhibitors against prostate cancer along with their molecular mechanism and biological mode of actions behind the anticancer efficacy.

Background: Cancer is the uncontrolled growth of abnormal cells in any part of the body. These abnormalities in the cells make them cancer cells, malignant cells, or tumour cells. These cells can infiltrate normal body tissues. Prostate Cancer begins when cells in the prostate gland start to grow out of control. Introduction: According to the National Cancer Institute, an estimated 20 percent of men experience Prostate Cancer in their lifetimes. Prostate Cancer can be divided into castration sensitive or hormone- sensitive Prostate Cancer (CSPC or HSPC) and castration-resistant Prostate Cancer (CRPC). Different therapies showed potential for the treatment of Prostate Cancer in that androgen receptor antagonist, cytochrome p17 inhibitors, radiation therapy, brachytherapy, surgical removal of the gland, androgen deprivation therapy and LnRH antagonists are some of the important ones. Despite various available treatment options in our understanding of the biological basis of Prostate Cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Several Tyrosine kinase inhibitors (TKIs) have been evaluated in the preclinical setting in Advanced Prostate Cancer. TKIs are small drug molecules that work by competitive ATP inhibition at the catalytic binding site of tyrosine kinase. This results in complete inhibition of the catalytic activity of certain enzymes. If chosen correctly, TKIs can target and inhibit critical, mutated pathways important for the development, progression and metastasis of Prostate Cancer. The review focuses on various tyrosine kinase drug targets and their chemical structure to discuss the mechanism and pathways in the treatment of Prostate Cancer. Methods: The method adopted for the study was mainly based on the secondary search through a systematic literature review. Targets discussed in this review include the epidermal growth factor family (EGFR), vascular endothelial growth factor family (VEGF) receptor, c-Src family kinases (Proto-oncogene tyrosine-protein kinase) (c-Src), platelet-derived growth factor (PDGF) and cmesenchymal- epithelial transition factor (c-Met), which showed some promising results in various studies. Results: Even with the strong scientific rationale for many TKIs in the treatment of Prostate Cancer, the clinical trial experience showed some negative results in advanced phases. However, despite various challenges, the validation studies targeting kinases hold great potential in Prostate Cancer. Given the success of kinase inhibitors across multiple other cancer types, it is likely that this drug class will eventually improve outcomes in Prostate Cancer. Conclusion: Modifications in structures and certain other aspects of TKIs may make these agents promising for the treatment of Prostate Cancer.