CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity.

The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808).

Measuring the impact of an educational intervention in rheumatoid arthritis: An open-label, randomized trial.

Objectives: This study aims to determine whether patients with active rheumatoid arthritis (RA), either starting on or changing biological or targeted synthetic disease-modifying antirheumatic drugs (DMARDs), demonstrate better self-management safety skills three months after receiving a multidisciplinary educational intervention compared to patients receiving usual care. Patients and methods: Between October 2015 and October 2018 , this open-label, randomized-controlled trial included a total of 107 RA patients (27 males, 80 females; mean age: 60.2±10.4 years; range, 54 to 71 years) who were on treatment or in whom treatment was changed with a biological or targeted synthetic DMARD. The patients were randomized into two groups: Group 1 (n=57) received additional intervention with educational DVD and one teleconference session and Group 2 (n=55) received usual care and were offered the intervention at three months. All patients underwent a final visit at six months. At each visit, the patients completed the BioSecure questionnaire measuring the self-care safety skills, a behavioral intention questionnaire, and the Beliefs about Medicines Questionnaire (BMQ). Results: No significant difference was observed in the Biosecure score at three months between the two groups (p=0.08). After pooling the first three-month data in Group 1 and the last three-month data in Group 2, the mean score of the BioSecure questionnaire increased to 7.10±0.92 in the group receiving educational intervention (p<0.0001). This increase was maintained at six months in Group 2 (p=0.88). The rate of appropriate behavioral intention increased over time (76% at baseline and 85% at six months for both groups). There was no significant change in the BMQ (p=0.44 to 0.84). Conclusion: The development of an educational DVD followed by a teleconference seem to improve self-care safety skills of the patients in practical situations.

Synthesis of a trans,syn,trans-dodecahydrophenanthrene via a bicyclic transannular Diels-Alder reaction: intermediate for the synthesis of fusidic acid.

While thermolysis of the macrobicyclic triene lactone 12 did not produce the expected bicyclic transannular Diels-Alder (BTADA) product 13, heating the corresponding ether 18 to 110 °C for 4 h afforded a quantitative yield of the desired cycloadduct 19, which could be easily reduced to the perhydrophenanthrene, an ABC ring analogue of fusidic acid 1. Theoretical calculations with hybrid density functional theory (B3LYP/6-31G(d)) help rationalize why the lactone does not cyclize whereas the ether does.

Studies toward the total syntheses of cucurbitacins B and D.

Synthetic efforts toward the convergent construction of the tetracyclic triterpenoids cucurbitacins B and D are described. The results of a Diels-Alder study examining the effects of steric and electronic variations of 2-methyl-2-cyclohexenone on the endo/exo-diastereoselectivity of the reaction are presented. The diastereomer of the core of the cucurbitacins, epimeric at C8, C9, and C10, 51, was synthesized via a highly regio- and stereoselective Diels-Alder reaction of the diene 4 and the novel dienophile 50.