Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond.

Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer-the most dreadful cancer so far.

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies.

Mutations of RAS oncogenes are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation to generate solid tumors in many types of cancer such as pancreatic carcinoma (over 80%), colon carcinoma (40-50%), lung carcinoma (30-50%), and other types of cancer. Once described as 'undruggable', RAS proteins have become 'druggable', at least to a certain extent, due to the continuous efforts made during the past four decades. In this account, we discuss the chemistry and biology (wherever available) of the small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins that were published in the past decades. Commercial drugs, as well as investigational molecules from preliminary stages to clinical trials, are categorized and discussed in this study. In summary, this study presents an in-depth discussion of RAS proteins, classifies the RAS superfamily, and describes the molecular mechanism of small-molecule RAS inhibitors.

Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations.

World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs). Chagas' disease (also known as American trypanosomiasis) and leishmaniasis are two major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas' disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski's "Rule of 5". Benzopyrazines 3 and 4 demonstrated moderate leishmanicidal activity against L. mexicana (M378) strain. The selective lead compound 1 showed good leishmanicidal, and trypanocidal activities (in vitro) against both L. mexicana (M378) and T. cruzi (NINOA) strains compared to the standard controls. The in vitro trypanocidal and leishmanicidal activities of the lead compound 1 have been validated by molecular docking studies against four biomolecular drug targets viz. T. cruzi histidyl-tRNA synthetase, T. cruzi trans-sialidase, leishmanial rRNA A-site, and leishmania major N-myristoyl transferase.