Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

A series of C 2 -symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein−protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. C 2 -symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC 50 values of 25 and 3.0 nM, respectively, in the HTRF assay. While 2a was ∼3.8-fold more potent than previously reported inhibitor 1a, 2b could not be differentiated from 1b due to their high potency and the limit of our HTRF assay conditions. In one cell-based coculture PD-1 signaling assay, 2a and 2b were 8.2-and 2.8-fold more potent in inhibiting PD-1 signaling than 1a and 1b, respectively. NMR and X-ray cocrystal structural studies provided more structural insights into the interaction between 2b and PD-L1; 2b binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than that previously reported for other inhibitors.

Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR’s kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors. Graphical abstract

No abstract

No abstract

No abstract

Breast cancer accounts for one of the most common causes of cancer-related deaths in women. Despite the available treatment modalities to cure breast cancer, therapeutic resistance and recurrence remain major challenges, owing to the culminating evidence of the presence of cancer stem cell subpopulations in breast tumors. The purpose of the study is to identify chemopreventive and dietary compounds that effectively target cancer stem cells to inhibit breast cancer development and progression. The mammosphere culture system has been proven to enrich cancer stem-like cells, and cells from mammospheres are shown to be more tumorigenic in vivo. By culturing mammospheres from breast cancer cell lines, we have shown that 1,25 vitamin D3, a vitamin D3 analog, BXL0124, pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene), tocopherols and triterpenoids (CDDO-Im) decreased the mammosphere forming efficiency (MFE) in a dose-dependent manner. Vitamin D compounds (1,25D3 and BXL0124) decreased the MFE in SUM159, MCF10DCIS and MCF-7 breast cancer cell lines (dose range 1-100 nM). Pterostilbene, a bioactive component of blueberries, effectively decreased the MFE in the MCF-7 cell line. The size of the mammospheres was found to be smaller with increasing concentrations (10-100 μM). Tocopherols significantly decreased estrogen-stimulated MFE in MCF-7 cells (1-10 μM). CDDO-Im, a synthetic triterpenoid derived from natural oleanolic acid, has also been shown to decrease MFE and sphere size in MCF-7 cells (50-100 nM). The effect on the shape of the spheres was also observed, suggesting the differentiation-inducing properties of these compounds. Taken together, we demonstrate that naturally occurring compounds as well as synthetic analogs derived from natural and dietary compounds significantly inhibit sphere forming efficiency and cancer stemness in breast cancer cells. Our study suggests that chemopreventive compounds, 1,25D3, BXL0124, pterostilbene, tocopherols, and CDDO-Im, are agents with the potential to target cancer stem-like cells to prevent breast cancer. Citation Format: Naing Lin Shan, Jeffrey Yang, Min Ji Bak, Joseph Wahler, Nanjoo Suh. Targeting cancer stem cells with chemopreventive agents for breast cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 276.

No abstract