Identification of Novel Covalent XPO1 Inhibitors Based on a Hybrid Virtual Screening Strategy.

Nuclear export protein 1 (XPO1), a member of the nuclear export protein-p (Karyopherin-P) superfamily, regulates the transport of "cargo" proteins. To facilitate this important process, which is essential for cellular homeostasis, XPO1 must first recognize and bind the cargo proteins. To inhibit this process, small molecule inhibitors have been designed that inhibit XPO1 activity through covalent binding. However, the scaffolds for these inhibitors are very limited. While virtual screening may be used to expand the diversity of the XPO1 inhibitor skeleton, enormous computational resources would be required to accomplish this using traditional screening methods. In the present study, we report the development of a hybrid virtual screening workflow and its application in XPO1 covalent inhibitor screening. After screening, several promising XPO1 covalent molecules were obtained. Of these, compound 8 performed well in both tumor cell proliferation assays and a nuclear export inhibition assay. In addition, molecular dynamics simulations were performed to provide information on the mode of interaction of compound 8 with XPO1. This research has identified a promising new scaffold for XPO1 inhibitors, and it demonstrates an effective and resource-saving workflow for identifying new covalent inhibitors.

Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells.

Multiple myeloma (MM) is a highly malignant hematologic cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC50 = 24 nM in MM.1S). In addition, the treatment with D4 significantly induced MM.1S cell cycle arrested and cell apoptosis, which was confirmed as on-target effect by immunofluorescence microscopy and competitive binding assay. Moreover, D4 displayed good metabolic stability over rat plasma and liver microsomes, as well as good pharmacokinetic profile on SD rat model with high drug exposure and decent bioavailability by oral gavage. All these good properties of D4 pave the way for further drug development and clinical application.

An updated patent review of Akt inhibitors (2016-present).

Introduction: Akt is a widely known serine threonine kinase involved in a series of critical cellular pathways like cell survival and proliferation. With the development of small-molecule Akt inhibitors, new strategies such as covalent, peptide-based, and PROTAC (Proteolysis Targeting Chimera) strategies have also been used the design of Akt inhibitors. On the other hand, due to the specificity of the Akt pathway, the use of Akt modulators in combination therapy and immunotherapy has been disclosed in the past 5 years.Areas covered: This review focuses on the patent literature covering small-molecule inhibitors of Akt kinase and their applications from 2016-present.Expert opinion: Although Akt inhibitors' progress has been somewhat slow over the past five years, new strategies still provide new opportunities for the development of Akt inhibitors. Combination with Akt pathway inhibitors for tumor therapy has also been widely disclosed in patents in the last 5 years. Notably, combination strategies of Akt inhibitors and immunotherapy have started to emerge in recent years. While the clinical indications of Akt modulators should not be limited to anti-cancer, it is still worth trying the treatment of other diseases. Within the next years, current drug development around Akt inhibitors should be fascinating.

If small molecules immunotherapy comes, can the prime be far behind?

Anti-cancer immunotherapy, which includes cellular immunotherapy, immune checkpoint inhibitors and cancer vaccines, has transformed the treatment strategies of several malignancies in the past decades. Immune checkpoints blockade (ICB) is the most commonly tested therapy and has the potential to induce a durable immune response in different types of cancers. However, all approved immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs), which are fraught with disadvantages including lack of oral bioavailability, prolonged tissue retention and poor membrane permeability. Therefore, the research focus has shifted to developing small molecule inhibitors to obviate the limitations of mAbs. Given the complexity of the tumor micro-environment (TME), the combination of ICIs with various small molecule agonists/inhibitors are currently being tested in clinical trials to improve treatment outcomes and prevent tumor recurrence. In this review, we have summarized the mechanisms and therapeutic potential of several molecular targets, along with the current status of small molecule inhibitors.

Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells.

The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development.