Arindam Sarkar

Progress in immuno-oncology has been stymied by poorly immunogenic 'cold' tumours and the focus on T cells at the cost of other immune cells. Here we report that AT-1965, a small molecule in a lipid nanoparticle, induces rapid regression of poorly immunogenic tumours with the formation of immune memory through interaction with Cap-specific RNA (nucleoside-2'-O-)-methyltransferase 2 (CMTR2) in cancer cells, triggering an innate inflammatory viral defence response. AT-1965-treated tumours were found to be highly infiltrated with B cells, which are known to act as early responders to viral signatures. Genetic knockout of functional B cells abrogated the anti-tumour efficacy of AT-1965, directly implicating B cells in the anti-tumour outcome. Our results rationalize clinical data showing that patients with high CMTR2 expression in tumours have a poor prognosis and that B cell infiltration is associated with long-term survival in multiple tumour types. The AT-1965 nanomedicine-inspired discovery of CMTR2 as a potential cancer target and B cell recruitment opens a new frontier for immuno-oncology.

Significant efforts have been made to develop new platinum anticancer compounds since the discovery of cis-platin; however, non-specific toxicity or loss of efficacy remain some of the major challenges in this area of platinum drug discovery. Newly developed platinum compounds, structurally distinct from the current molecules, imparting efficacy at lower concentrations than the current drugs, and interacting with DNA leading to cell death, may prove beneficial. In the current study, we designed, synthesized, and characterized three phenalenyl based platinum chloride compounds (1, 2, and 3) with the goal that a labile Pt–Cl bond with the planar structure of the phenalenyl moiety would enhance their interaction with DNA, leading to improved efficacy. In addition, it is assumed that the fluorescent properties of these compounds would facilitate mechanistic investigation. The crystal structure of compound 1 demonstrates a perfectly planar structure with a single Pt–Cl bond. In vitro cell viability studies on cancer cell lines, including lung, colorectal, breast, and osteosarcoma, revealed a superior efficacy for compounds 1 and 2, relative to platinum drugs in clinical use. Localization studies utilized the strong fluorescence of compound 3 to investigate the mechanism of action, revealing its interaction with DNA, leading to cell death. This study enriches the arsenal of potential platinum-based anti-cancer therapeutics and provides an easy-to-use tool for the mechanism-of-action studies of these compounds.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antibody–drug conjugates (ADCs) combine the high specificity of antibodies with cytotoxic payloads. However, the present strategies for the synthesis of ADCs either yield unstable or heterogeneous products or involve complex processes. Here, we report a computational approach that leverages molecular docking and molecular dynamics simulations to design ADCs that self-assemble through the non-covalent binding of the antibody to a payload that we designed to act as an affinity ligand for specific conserved amino acid residues in the antibody. This method does not require modifications to the antibody structure and yields homogenous ADCs that form in less than 8 min. We show that two conjugates, which consist of hydrophilic and hydrophobic payloads conjugated to two different antibodies, retain the structure and binding properties of the antibody and its biological specificity, are stable in plasma and improve anti-tumour efficacy in mice with non-small cell lung tumour xenografts. The relative simplicity of the approach may facilitate the production of ADCs for the targeted delivery of cytotoxic payloads.

Diaminocyclohexane-Pt(II)-phenalenyl complexes (1 and 2) showed an appropriate balance between efficacy and toxicity. Compound 2 showed nearly two-fold higher tumour growth inhibition than oxaliplatin in a murine NSCLC tumour model, when a combined drug development approach was used. The fluorescent properties of phenalenone were utilized to understand the mechanistic details of the drug.

The synthesis and pH‐sensing property of a novel phenalenone‐based compound, 9‐(4‐hydroxyphenylamino)‐1‐oxo‐phenalenone (HPAP), is reported. The newly synthesized compound is capable of functioning as a pH sensor in the region of pH 7 to 12. The sensor can be used as a colorimetric indicator in the transition from pH 10 to pH 11. The sensor is able to function in four detectable channels. All four channels (UV, emission, colorimetric/visible and photoluminescence) have been shown to be reversible, thus implying the reuse of this single‐molecule sensor and indicator for several experiments. Mechanistic investigations have been performed by UV, NMR and DFT studies which indicate that a photoinduced electron transfer (PET) based mechanism could be operative. Straightforward and cost‐effective application of the sensor in thin‐layer chromatography has also been established.

Since the approval of cisplatin in 1979, platinum-based drugs have been regularly used in cancer chemotherapy as a first-line treatment or with the combination of other nonplatinum drugs. Subsequent approval of second- and third-generation drugs such as carboplatin and oxaliplatin respectively, has widened the therapeutic achievement of platinum compounds. There are few other platinum drugs approved recently and many other new drugs as well as the formulations of the old ones are going through clinical trials now. Considering the astonishing achievement of these drugs, analyses on the overall scenario of the patent applications on platinum compounds have become the priority to the scientific community. This review summarizes the published patent applications on the novel platinum anticancer compounds from 2012 to 2017 (August).

Despite the advances in the design of antibody–drug conjugates (ADCs), the search is still ongoing for novel approaches that lead to increased stability and homogeneity of the ADCs. We report, for the first time, an ADC platform technology using a platinum(II)-based linker that can re-bridge the inter-chain cysteines in the antibody, post-reduction. The strong platinum–sulfur interaction improves the stability of the ADC when compared with a standard maleimide-linked ADC thereby reducing the linker–drug exchange with albumin significantly. Moreover, due to the precise conserved locations of cysteines, both homogeneity and site-specificity are simultaneously achieved. Additionally, we demonstrate that our ADCs exhibit increased anticancer efficacy in vitro and in vivo. The Pt-based ADCs can emerge as a simple and exciting proposition to address the limitations of the current ADC linker technologies.

153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. Methods: Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. Results: We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. Conclusions: Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.