Editorial : Chemical Biology Tools for Peptide and Protein Research

Non peer reviewe

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products.

yesCC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products.EPSRC, Yorkshire Cancer Research, Big C Cancer Research, UCB Pharm

2,6-Diphenyl-imidazopyridine derivatives as novel prototypes of anticancer agents targeting aldehyde dehydrogenase

Aldehyde dehydrogenase (ALDH) superfamily comprises 19 different enzyme types located in specific subcellular districts, including cytosol and mitocondria. Their main function is to oxidize endogenous and exogenous aldehydes produced in human cells. In particular, isoforms 1A1, 1A2 and 1A3 catalyze the transformation of retinal into retinoic acid, which is a potent differentiation tissue factor for cellular development. Overexpression of these three isoforms in cancer stem cells (CSC), underlined in recent studies, is to date extremely important in cancer field, as it offers the chance to use these proteins both as prognostic marker and as novel targets in the fight against cancer. Here we present a novel series of 2,6-diphenyl-imidazol[1,2-a]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structured-based optimizations of a previously developed lead, GA11. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family, and investigated through crystallization and modeling studies for their ability to interact with the catalytic site of the 1A3 isoform. Tested in vitro on different populations of CSCs, obtained from glioma, colorectal and prostate tissue specimens, they exhibited a relevant anti-proliferative efficacy, thus paving the way for treating cancer by means of the still untapped aldehyde dehydrogenases

Deep Learning-Based Segmentation of Cellular Membranes in Colorectal Immunohistochemical Images

The segmentation of cellular membranes is essential for getting crucial information in diagnosing several cancers, including lung, breast, colon, gastric cancer, etc. Manual segmentation of cellular membranes is a tedious, time-consuming routine and prone to error and inter-observer variation. So, it is one of the challenges that pathologists face in immunohistochemical (IHC) tissue images. Although automated segmentation of cellular membranes has recently gained considerable attention in digital pathology applications, little research is based on machine learning approaches. Therefore, this study proposes a deep framework for semantic segmenting cellular membranes using an end-to-end trainable Convolutional Neural Network (CNN) based on encoder and decoder architecture with Atreus Spatial Pyramid Pooling (ASPP). The backbone of the encoder depends on the residual architecture. The performance of the proposed framework was evalu ated and compared to other benchmark methods. As a result, we show that the proposed framework exhibits significant potential for cellular membranes segmentation in IHC images

Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

YesThe duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation in solid phase synthesis. The synthesis was performed on a large scale and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers. Application to solid phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine but this had no beneficial effects on biological activity.MJS was funded by Novartis and UEA. We thank the EPSRC Mass Spectrometry Service, Swansea. We thank Richard Robinson and Julia Hatto at Novartis for help in the large scale synthesis

Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties

An efficient four-step synthesis of tetracyclic lactones from 1,4-benzodioxine-2-carboxylic acid was developed. Ellipticine derivatives exhibit antitumor activity however only a few derivatives without carbazole subunit have been studied to date. Herein, several tetracyclic lactones were synthesized and biologically evaluated. Several compounds (2a, 3a, 4a and 5a) were found to be inhibitors of the KrasWnt pathway. The lactone 2a also exerted a potent inhibition of Tau protein translation and was shown to have capacity for CYP1A1-bioactivation. The results obtained are further evidence of the therapeutic potential of tetracyclic lactones related to ellipticine. Molecular modeling studies showed that compound 2a is inserted between helix a3 and a4 of the KRas protein making interactions with the hydrophobic residues Phe90, Glu91, Ile9364, Hie94, Leu133 and Tyr137and a hydrogen bond with residue Arg97

In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER0.01 of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER0.01 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER0.01 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER0.01 of 1.56-2.37 compared with AQ4N SER0.01 of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

YesTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes

Design, synthesis, biological evaluation and in silico study of benzyloxybenzaldehyde derivatives as selective aldh1a3 inhibitors

Altres ajuts: This research was funded by Al-Zaytoonah University of Jordan, grant number 2019- 2018/18/03 and by UoB International Development Fund Scheme PhD, grant code studentship to E.B. R.J. is a recipient of a PIF predoctoral fellowship from Universitat Autònoma de Barcelona.Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Therefore, finding selective inhibitors against ALDH1A3 could result in new treatment options for cancer treatment. In this study, ALDH1A3-selective candidates were designed based on the physiological substrate resemblance, synthesized and investigated for ALDH1A1, ALDH1A3 and ALDH3A1 selectivity and cytotoxicity using ALDH-positive A549 and ALDH-negative H1299 cells. Two compounds (ABMM- 15 and ABMM-16), with a benzyloxybenzaldehyde scaffold, were found to be the most potent and selective inhibitors for ALDH1A3, with IC50 values of 0.23 and 1.29 μM, respectively. The results also show no significant cytotoxicity for ABMM-15 and ABMM-16 on either cell line. However, a few other candidates (ABMM-6, ABMM-24, ABMM-32) showed considerable cytotoxicity on H1299 cells, when compared to A549 cells, with IC50 values of 14.0, 13.7 and 13.0μM, respectively. The computational study supported the experimental results and suggested a good binding for ABMM- 15 and ABMM-16 to the ALDH1A3 isoform. From the obtained results, it can be concluded that benzyloxybenzaldehyde might be considered a promising scaffold for further drug discovery aimed at exploiting ALDH1A3 for therapeutic intervention