Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth.

EphA2 receptor kinase could become a novel target for anti-glioblastoma treatment. Doxazosin previously identified acts like the endogenous ligand of EphA2 and induces cell apoptosis. Through lead structure modification a derivative of Doxazosin possessing unique dimeric structure showed an improvement in the activity. In the current study, we expanded the dimeric scaffold by lead optimization to explore the chemical space of the conjoining moieties and a slight variation to the core structure. 27 new derivatives were synthesized and examined with EphA2 overexpressed and wild type glioblastoma cell lines for cell proliferation and EphA2 activation. Three new compounds 3d, 3e, and 7bg showed potent and selective activities against the growth of EphA2 overexpressed glioblastoma cells. Dimer 3d modification replaces the long alkyl chain with a short polyethylene glycol chain. Dimer 7bg has a relatively longer polyethylene glycol chain in comparison to compound 3d and the length is more similar to the lead compound. Whereas dimer 3e has a rigid aromatic linker exploring the chemical space. The diversity of the linkers in the active suggest additional hydrogen binding sites has a positive correlation to the activity. All three dimers showed selective activity in EphA2 overexpressed cells, indicating the activity is correlated to the EphA2 targeting effect.

Acute keratoconjunctivitis associated with tisotumab vedotin-tftv for metastatic cervical cancer.

Purpose: Tisotumab vedotin-tftv, an antibody-drug conjugate, was recently FDA-approved for metastatic or treatment-resistant cervical cancer. A high rate of ocular comorbidities was seen in pivotal clinical trials. We present a case of a 46-year-old woman who experienced prolonged ocular surface adverse effects associated with use of the drug. Observations: Our patient was initiated on tri-weekly 2mg/kg infusions of tisotumab for metastatic cervical cancer. Baseline ophthalmic exam was unremarkable. One week after the second infusion, she developed bilateral eyelid edema and chalazia managed with initiation of lid hygiene measures. Preceding the fourth infusion, she developed unilateral pseudomembranous conjunctivitis and bilateral meibomitis that improved with topical corticosteroids. The fifth infusion was subsequently given at a reduced dosage. Despite this, she experienced decreased vision, bilateral diffuse punctate epitheliopathy, and subepithelial haze. The patient was subsequently referred to the cornea service. Symptomatic and clinical improvement was initially achieved with the addition of bandage contact lenses (BCLs). As the keratitis improved, topical steroids were tapered and BCLs removed. She is currently maintained on a regimen that includes eyelid hygiene, preservative-free artificial tears, punctal plugs, autologous serum tears, and lifitegrast. Given the severity of the ophthalmic adverse effects, however, further tisotumab infusions were held. Conclusions and importance: This is a report of a patient with prolonged ocular surface disease following the initiation of tisotumab, significant enough to lead to discontinuation. Antibody-drug conjugates are an emerging class of therapeutics across oncology, and ophthalmologists should be aware of their potential effects on ocular health.

Identification of Prazosin as a Potential Flagellum Attachment Zone 1(FAZ1) Inhibitor for the Treatment of Human African Trypanosomiasis.

Human African trypanosomiasis (HAT) remains a health threat to sub-Saharan Africa. The current treatments suffer from drug resistance and life-threatening side effects, making drug discovery for HAT still important. A high-throughput screening of the library of pharmaceutically active compounds identified prazosin, an α-adrenoceptor antagonist, that showed selective activity toward Trypanosoma brucei brucei. Furthermore, a series of prazosin analogues were examined, and overall, the new analogues had improved activity and selectivity. To elucidate the binding partner, a biotin-conjugated probe was synthesized, and a protein pulldown assay combined with a proteomic analysis identified the flagellum attachment zone 1 (FAZ1) filament as an interacting partner. Additionally, prazosin treatment resulted in dysfunction of the flagellum of trypanosome cells, which is indicative of a FAZ1 irregularity. We also examined the drug distribution by utilizing immunofluorescence with a designed fluorescent analogue that showed partial colocalization with FAZ1. With the activity of the prazosin analogues, a structure-activity relationship (SAR) was summarized for future lead optimization. Our findings provide a new group of FAZ1 inhibitors as novel antitrypanosomal agents.