Identification and Targeting of Novel Mechanisms for Treatment of Castration Resistant Prostate Cancer (CRPC)

Prostate cancer (PCa) is a significant contributor to cancer-related deaths among men globally, with varying prevalence across regions, particularly higher rates in North America, Europe, and Australia. The disease's incidence escalates with age, emphasizing its relevance in aging populations. PCa cells are fueled by androgens through the Androgen Receptor (AR), which activates genes crucial for tumor growth and survival. Thus, reducing circulating androgen levels or blocking AR remains primary in PCa treatment. However, in advanced stages like Castration-Resistant Prostate Cancer (CRPC), tumor cells develop mechanisms to thrive independently of androgens. These mechanisms involve the production of androgens within the tumor itself, highlighting androgen biosynthesis as a key target for CRPC treatment. Androgens, primarily produced in the testes, ovaries, and adrenal glands, regulate male sexual traits and behaviors. The adrenal cortex's Zona Reticularis (ZR) produces precursor hormones like dehydroepiandrosterone (DHEA) and its sulfate, which serve as substrates for androgen production. Cytochrome P450c17 (CYP17A1) plays a pivotal role in adrenal androgen production, catalyzing essential reactions in steroidogenesis. Given its significance, inhibiting CYP17A1 has garnered interest in PCa treatment. Abiraterone, a CYP17A1 inhibitor, albeit effective, lacks specificity and affects other CYP enzymes. Recent discoveries, like mutations abolishing CYP17A1's specific lyase activity, offer hope for developing selective inhibitors. Efforts focus on designing molecules targeting CYP17A1 without resembling androgens to avoid inadvertently stimulating androgen receptor signaling. Small molecule inhibitors are being screened, including those computationally designed to mimic native substrates. Additionally, exploration into endocrine disruptors' role in inhibiting CYP17A1 activity provides insights into environmental factors influencing cancer risk. Understanding the regulation of CYP17A1 activity through phosphorylation pathways offers another avenue. Kinases such as p38α and ROCK1, along with phosphatases like PP2A, play roles in modulating CYP17A1 activity. PLK1 inhibition demonstrated decreased CYP17A1 lyase activity, suggesting its potential as a target. Transcriptomic analysis identified differentially expressed kinases and phosphatases in PCa and polycystic ovary syndrome (PCOS), shedding light on potential therapeutic targets. Insights into CYP17A1 regulation also have implications beyond PCa, extending to hyperandrogenic disorders like PCOS and premature adrenarche. Developing drugs to lower androgen levels without affecting cortisol can mitigate side effects seen with current therapies, offering broader applications in reproductive health. In conclusion, targeting CYP17A1 holds promise in PCa treatment, especially in CRPC. Advances in understanding its regulation and identifying specific inhibitors offer hope for more effective therapies. Moreover, insights into CYP17A1's role in hyperandrogenic disorders present opportunities for broader therapeutic interventions in reproductive health

Catalytic Philanthropy In India

Catalytic Philanthropy is still in its infancy in India. Despite this, there are a surprising number of exemplary cases where Indian philanthropists are creating large-scale social change far beyond the resources invested. This report highlights these practices as well as the key issues that need to be addressed to accelerate its evolution

Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment.

CYP17A1 is an enzyme that plays a major role in steroidogenesis and is critically involved in the biosynthesis of steroid hormones. Therefore, it remains an attractive target in several serious hormone-dependent cancer diseases, such as prostate cancer and breast cancer. The medicinal chemistry community has been committed to the discovery and development of CYP17A1 inhibitors for many years, particularly for the treatment of castration-resistant prostate cancer. The current Perspective reflects upon the discovery and evaluation of non-steroidal CYP17A1 inhibitors from a medicinal chemistry angle. Emphasis is placed on the structural aspects of the target, key learnings from the presented chemotypes, and design guidelines for future inhibitors

Synthesis and Structure-Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents.

Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure-activity relationship of this novel non-steroidal compound class

Essential oil metabolites can regulate adrenal androgen production by inhibition of CYP17A1 activities.

Endocrine-disrupting chemicals (EDCs) can affect human steroid metabolism. Previous clinical case reports have shown that some Essential Oils (EOs) like lavender oil and tea tree oil may act as potential EDCs and are linked to prepubertal gynecomastia in boys and premature thelarche in girls due to regular exposure to lavender based fragrances among Hispanic population. These studies suggested role of EOs in steroid metabolism in humans. We have screened a range of EO metabolites for effects on androgen production by CYP17A1. For preliminary screening, human adrenal NCI H295R cells were treated with 10 µM of test compounds for 24 hours. The test compounds had been extracted and purified from natural resources and are found as major components in EOs. For CYP17A1 activity, the conversion of radiolabelled substrate, 17-Hydroxy-pregnenolone to Dehydroepiandrosterone was determined using tritiated water release assay. Eucalyptol, Dihydro-β-Ionone, (-)-α-pinene were extracted from eucalyptus, rose and pine resin. Out of about 50 test compounds, eucalyptol, Dihydro-β-Ionone & (-)-α-pinene showed 20% to 40% inhibition of DHEA production. Rest of the compounds showed either no or low inhibition. Some compounds were also tested for effects on CYP19A1 (aromatase) activity where upto 30% inhibition was observed. EOs are often used in various beauty and hygiene products as they have few known side-effects. However, prolonged exposure to these products may result in steroid imbalance. Due to their anti-androgenic activity, these compounds should be studied further as chemical leads for the treatment of hyperandrogenic disorders such as Prostate cancer and Polycystic ovary syndrome

Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy.

Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis and is often highly expressed in cancer cells. We found that FASN mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34+ hematopoietic progenitors. Accordingly, FASN levels decreased during all-trans retinoic acid (ATRA)-mediated granulocytic differentiation of acute promyelocytic leukemia (APL) cells, partially via autophagic degradation. Furthermore, our data suggest that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG) accelerated the differentiation of APL cell lines and significantly re-sensitized ATRA refractory non-APL AML cells. FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis. Together, our data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells

Effect of Essential Oil Components on the Activity of Steroidogenic Cytochrome P450

Endocrine-disrupting chemicals (EDCs) may impact the development of prostate cancer (PCa) by altering the steroid metabolism. Although their exact mechanism of action in controlling tumor growth is not known, EDCs may inhibit steroidogenic enzymes such as CYP17A1 or CYP19A1 which are involved in the production of androgens or estrogens. High levels of circulating androgens are linked to PCa in men and Polycystic Ovary Syndrome (PCOS) in women. Essential oils or their metabolites, like lavender oil and tea tree oil, have been reported to act as potential EDCs and contribute towards sex steroid imbalance in cases of prepubertal gynecomastia in boys and premature thelarche in girls due to the exposure to lavender-based fragrances. We screened a range of EO components to determine their effects on CYP17A1 and CYP19A1. Computational docking was performed to predict the binding of essential oils with CYP17A1 and CYP19A1. Functional assays were performed using the radiolabeled substrates or Liquid Chromatography–High-Resolution Mass Spectrometry and cell viability assays were carried out in LNCaP cells. Many of the tested compounds bind close to the active site of CYP17A1, and (+)-Cedrol had the best binding with CYP17A1 and CYP19A1. Eucalyptol, Dihydro-β-Ionone, and (−)-α-pinene showed 20% to 40% inhibition of dehydroepiandrosterone production; and some compounds also effected CYP19A1. Extensive use of these essential oils in various beauty and hygiene products is common, but only limited knowledge about their potential detrimental side effects exists. Our results suggest that prolonged exposure to some of these essential oils may result in steroid imbalances. On the other hand, due to their effect on lowering androgen output and ability to bind at the active site of steroidogenic cytochrome P450s, these compounds may provide design ideas for novel compounds against hyperandrogenic disorders such as PCa and PCOS

Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

This study reports on the synthesis and evaluation of novel compounds replacing the nitrogen-containing heterocyclic ring on the chemical backbone structure of cytochrome P450 17α-hydroxylase/12,20-lyase (CYP17A1) inhibitors with a phenyl bearing a sulfur-based substituent. Initial screening revealed compounds with marked inhibition of CYP17A1 activity. The selectivity of compounds was thereafter determined against cytochrome P450 21-hydroxylase, cytochrome P450 3A4, and cytochrome P450 oxidoreductase. Additionally, the compounds showed weak inhibitory activity against aldo-keto reductase 1C3 (AKR1C3). The compounds’ impact on steroid hormone levels was also assessed, with some notable modulatory effects observed. This work paves the way for developing more potent dual inhibitors specifically targeting CYP17A1 and AKR1C3