Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma characterized by poor prognosis. The complexity of MCL pathogenesis arises from aberrant activities of diverse signaling pathways, including BTK, PI3K–AKT–mTOR and MYC-BRD4. Here, we report that MCL-related signaling pathways can be altered by a single small molecule inhibitor, SRX3305. Binding and kinase activities along with resonance changes in NMR experiments reveal that SRX3305 targets both bromodomains of BRD4 and is highly potent in inhibition of the PI3K isoforms α, γ and δ, as well as BTK and the drug-resistant BTK mutant. Preclinical investigations herein reveal that SRX3305 perturbs the cell cycle, promotes apoptosis in MCL cell lines and shows dose dependent anti-proliferative activity in both MCL and drug-resistant MCL cells. Our findings underscore the effectiveness of novel multi-action small molecule inhibitors for potential treatment of MCL.

Identification of Molecular Subtypes and Potential Small-Molecule Drugs for Esophagus Cancer Treatment Based on m6A Regulators

Background. Esophagus cancer (ESCA) is the sixth most frequent cancer in males, with 5-year overall survival of 15%–25%. RNA modifications function critically in cancer progression, and m6A regulators are associated with ESCA prognosis. This study further revealed correlations between m6A and ESCA development. Methods. Univariate Cox regression analysis and consensus clustering were applied to determine molecular subtypes. Functional pathways and gene ontology terms were enriched by gene set enrichment analysis. Protein-protein interaction (PPI) analysis on differentially expressed genes (DEGs) was conducted for hub gene screening. Public drug databases were employed to study the interactions between hub genes and small molecules. Results. Three molecular subtypes related to ESCA prognosis were determined. Based on multiple analyses among molecular subtypes, 146 DEGs were screened, and a PPT network of 15 hub genes was visualized. Finally, 8 potential small-molecule drugs (BMS-754807, gefitinib, neratinib, zuclopenthixol, puromycin, sulfasalazine, and imatinib) were identified for treating ESCA. Conclusions. This study applied a new approach to analyzing the relation between m6A and ESCA prognosis, providing a reference for exploring potential targets and drugs for ESCA treatment.

Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.

A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types

To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.

Efficient generation of lower induced Motor Neurons by coupling Ngn2 expression with developmental cues

Human pluripotent stem cells (hPSCs) are a powerful tool for disease modelling and drug discovery, especially when access to primary tissue is limited, such as in the brain. Current neuronal differentiation approaches use either small molecules for directed differentiation or transcription-factor-mediated programming. In this study we coupled the overexpression of the neuralising transcription factor Neurogenin2 (Ngn2) with small molecule patterning to differentiate hPSCs into lower induced Motor Neurons (liMoNes). We showed that this approach induced activation of the motor neuron (MN) specific transcription factor Hb9/MNX1, using an Hb9::GFP-reporter line, with up to 95% of cells becoming Hb9::GFP+. These cells acquired and maintained expression of canonical early and mature MN markers. Molecular and functional profiling revealed that liMoNes resembled bona fide hPSC-derived MN differentiated by conventional small molecule patterning. liMoNes exhibited spontaneous electrical activity, expressed synaptic markers and formed contacts with muscle cells in vitro. Pooled, multiplex single-cell RNA sequencing on 50 cell lines revealed multiple anatomically distinct MN subtypes of cervical and brachial, limb-innervating MNs in reproducible quantities. We conclude that combining small molecule patterning with Ngn2 can facilitate the high-yield, robust and reproducible production of multiple disease-relevant MN subtypes, which is fundamental in the path to propel forward our knowledge of motoneuron biology and its disruption in disease.

Mechanically Strong and Tailorable Polyimide Aerogels Prepared with Novel Silicone Polymer Crosslinkers

Polyimide (PI) aerogels were prepared using self-designed silicone polymer cross-linkers with multi-amino from low-cost silane coupling agents to replace conventional small-molecule cross-linkers. The long-chain structure of silicone polymers provides more crosslinking points than small-molecule cross-linkers, thus improving the mechanical properties of polyimide. To investigate the effects of amino content and degree of polymerization on the properties of silicone polymers, the different silicone polymers and their cross-linked PI aerogels were prepared. The obtained PI aerogels exhibit densities as low as 0.106 g/cm3 and specific surface areas as high as 314 m2/g, and the maximum Young’s modulus of aerogel is up to 20.9 MPa when using (T-20) as cross-linkers. The cross-linkers were an alternative to expensive small molecule cross-linkers, which can improve the mechanical properties and reduce the cost of PI aerogels.