No abstract

Locked nucleic acid (LNA) is a chemically modified nucleic acid with its sugar ring locked in an RNA-like (C3′-endo) conformation. LNAs show extraordinary thermal stabilities when hybridized with DNA, RNA or LNA itself. We performed molecular dynamics simulations on five isosequential duplexes (LNA–DNA, LNA–LNA, LNA–RNA, RNA–DNA and RNA–RNA) in order to characterize their structure, dynamics and hydration. Structurally, the LNA–DNA and LNA–RNA duplexes are found to be similar to regular RNA–DNA and RNA–RNA duplexes, whereas the LNA–LNA duplex is found to have its helix partly unwound and does not resemble RNA–RNA duplex in a number of properties. Duplexes with an LNA strand have on average longer interstrand phosphate distances compared to RNA–DNA and RNA–RNA duplexes. Furthermore, intrastrand phosphate distances in LNA strands are found to be shorter than in DNA and slightly shorter than in RNA. In case of induced sugar puckering, LNA is found to tune the sugar puckers in partner DNA strand toward C3′-endo conformations more efficiently than RNA. The LNA–LNA duplex has lesser backbone flexibility compared to the RNA–RNA duplex. Finally, LNA is less hydrated compared to DNA or RNA but is found to have a well-organized water structure.

Nuclear-Factor kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB exists in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of physical, chemical, and biological stimuli leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (kappaB sites in the DNA), to initiate transcription. This transcription has been known to be involved in a number of diseases including cancer, AIDS, and inflammatory disorders. The present article focuses on two important issues of current and future interest- firstly a review of the main human diseases which are initiated due to NF-kappaB mediated transcription is presented. Next, comprehensive information on the current inhibitors which are targeted to interfere with the NF-kappaB pathway is provided. This latter section presents a critical review on different types of latest inhibitors targeting the complex NF-kappaB pathway at several stages. The inhibitors developed till date and still under investigation, include mainly those which interfere with the activation of NF-kappaB. Based on the complexity of NF-kappaB activation, and the current knowledge of the structural biology of NF-kappaB-DNA binding, finally it is proposed that a better approach to inhibit NF-kappaB induced transcription exists. In this context, a perspective is presented in the end, proposing de novo design of inhibitors which directly interact with the DNA Binding region of the free NF-kappaB (p50 subunit), so as to generate more specific and selective leads of NF-kappaB-DNA binding.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower risk myelodysplastic syndrome.JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent anti-proliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myeloid leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity driven tumors.