Recent Patents on Anti-Cancer Drug Discovery - Volume 12, Issue 4, 2017

Background: Notable progress has been made in chemo- and immunotherapy of B-cell lymphomas, but less in the treatment of T-cell lymphomas. Objective: Histone deacetylases inhibitors are a potentially useful therapeutic mean, as an epigenetic dysregulation is present in lymphomas, and especially in T-cell types. We aimed to study the progress made in this area. Method: A mini-review was achieved using the articles published in PubMed in the last two years and the new patents made in this field. Results: Histone deacetylases inhibitors are involved in the derepression of tumor suppressor genes through a histone deacetylase-mediated transcriptional process. Their inhibition is followed by cell cycle arrest, cell differentiation, apoptosis, sometimes autophagy, and a reversal of the transformed phenotype. They can also remove the resistance to chemo- or immunotherapy through different pathways. Some of them, as romidepsin, may decrease the protein level of multi-drug resistance associated protein 1, followed by a decrease in cellular drug export activity for DNA alkylating agents. Some compounds are approved for relapsed/refractory T-cell lymphomas or multiple myeloma treatment. The recent patents and the clinical trials with a histone deacetylases inhibitor administred in a synergistic drug combination with a demethylating, immunomodulatory, or anticancer agent as well as the discovery of more selective histone deacetylases inhibitors, with fewer side effects, could be a way to increase the treatment efficacy. Conclusion: New and more effective histone deacetylases inhibitors given alone or in drug combination are a solution for an improved response to the treatment of patients with relapsed/refractory lymphoproliferative disorders.

Background: FLT3 is a member of receptor tyrosine kinase III family, mainly expressed in hematopoietic cells. The aberrant expression and function of FLT3 are strongly related to leukemia, especially acute myeloid leukemia. Its varieties of amino-acid residues mutations, such as FLT3-ITDs and -TKDs, can induce constant proliferation of hematological tumor cells with poor prognosis. Hence FLT3 serves as a promising target in AML chemotherapy. Objective: This review focused on the progress of FLT3 inhibitors study including those that have entered clinical trials or were reported in numerous patents all over the world. Thus, we provided a useful reference for the development of new anti-leukemia drugs. Method: Through a comprehensive retrospective study, FLT3 inhibitors in several patent applications were identified and classified into five categories, including quinolone-related, indole-related, ureas, pyrimidines and other compounds. Results: For each category of compounds, the structural feature, SAR, biological activity and current research status were thoroughly reviewed and analyzed. Conclusion: Although some of those compounds expressed potent bioactivities and have reached the advanced clinical trials for the treatment of leukemia, there are still several problems need to be faced before they enter the market eventually, especially the drug resistance issue. The improvement of therapeutic potency for FLT3 inhibitors might depend on the useful combination therapy and further refinement of the intrinsic properties of FLT3 inhibitors.

Background: Epidermal Growth Factor Receptor (EGFR) is overexpressed in a variety of cancers and is associated with poor prognosis, low survival rate, and resistance of cancer cells to treatment. Objective: This review discusses the combined effect of EGFR inhibitor and radiation therapy in cancer treatment. Method: The recent literature and patent applications were considered in which the role of EGFR in cancer and EGFR inhibitors, as well as the preclinical and clinical studies are related to synergistic effects of EGFR inhibitors and ionizing radiation in the treatment of various cancers. Results: The specific inhibition has been introduced as targeted therapy for treatment of cancers. Two major pharmacological approaches for inhibition of EGFR are monoclonal antibodies and smallmolecule tyrosine kinase inhibitors. The use of these agents in combination with ionizing radiation results in increasing the cytotoxicity on tumors that are rich in expression of EGFR. Conclusion: The combination of EGFR inhibitor and ionizing radiation has synergistic effect and resulted in improvement of radiotherapy in patients.

Background: Bromodomain and Extra Terminal (BET) family of bromodomain proteins (BRDs), comprised of four members in humans (BRD2, BRD3, BRD4, and BRDT), has emerged as a promising new cancer target class for small-molecule drug discovery. Objective: This review discusses the patent literature of BET inhibitors (2010-2017) for the treatment of cancer and other related diseases. Method: BET proteins act as ‘epigenetic readers' and bind to acetylated lysine residues on the tails of histones H3 and H4. Inhibition of BET proteins for a wide array of therapeutic applications has led to the discovery and development of various BET inhibitors. Results: The increasing significance of BET inhibitors as a potential anticancer therapeutic has led to an extensive patent activity both from academia and pharmaceutical industry. Several of the BET inhibitors are under clinical development for the treatment of various kinds of cancers. Conclusion: The unmet needs and challenges associated with BET inhibition for cancer treatment have been portrayed in this review. An insight into the current developments and future prospects has been described as well.

Background: Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. There are numerous published patent applications till 2017. It was claimed that novel HDACIs were optimized as potential drug candidates, designed for regional or systemic release, and created as significant inhibitors. Objective: In the present study, 3D-QSAR and molecular docking were used to provide a theoretical basis for finding highly potent anti-tumor drugs. Methods: QSAR was used to generate models and predict the HDAC1 inhibitory activity using the Sybyl program (x1.2 version). Biaryl benzamides (n=73) as selective HDAC1 inhibitors were selected as our data set, which was split randomly into training (n=63) and test sets (n=10). Docking was carried out using the MOE software. Partial least square was used as QSAR model-generation method. External validation and cross-validation (leave-one-out and leave-10-out) were used as validation methods. Results: Both CoMFA (q2, 0.663; rncv 2 , 0.909) and CoMSIA models (q2, 0.628; rncv2 , 0.877) for training set yielded significant statistical results. The predictive ability of the derived models was examined by a test set of 10 compounds and external validation results displayed rpred 2 and rm 2 values of 0.767 and 0.664 for CoMFA and 0.722 and 0.750 for CoMSIA, respectively. Conclusion: The obtained models showed a good predictive ability in both internal and external validation and could be used for designing new biaryl benzamides as potent HDAC1 inhibitors in cancer treatment. The amido and amine groups of benzamide part as scaffold and the bulk groups as a hydrophobic part were key factors to improve inhibitory activity of HDACIs.

Background: Protoberberine isoquinoline alkaloids are found in many plant species. They consist of a diverse class of secondary metabolites with many pharmacologically active members, such as different derivatives of berberine already patented. In the development of approximately 20-25% of all cancers, altered hedgehog (Hh) signalling is involved where the smoothened (Smo) transmembrane receptor triggers Hh signalling pathway towards Gli1 gene expression. Objective: The current study aimed to model and verify the anti-Smo activity of berberine and its derivatives using a novel automated script. Method: Based on the patented inventions filed on ADMET modelling until 2016, which also predicts ADMET parameters and binding efficiency indices for all molecules, a script was developed to run automated molecular docking for a large number of small molecules. Results: Berberine was found to interact with Lys395 of Smo receptor via hydrogen bonding and cation-π interactions. In addition, π-π interactions between berberine aromatic rings and two aromatic residues in the Smo transmembrane domain, Tyr394 and Phe484, were noted. Binding efficiency indices using an in silico approach to plot the Smo-specific binding potency of each ligand was performed. The mRNA level of Gli1 was studied as the outcome of Hh signalling pathway to show the effect of berberine on hedgehog signalling. Conclusion: This study predicted the role of berberine as an inhibitor of Smo receptor, suggesting its effectiveness in hedgehog signalling during cancer treatment.