PF 06465469

Improved disease activity with fosdagrocorat (PF-04171327), a partial agonist of the glucocorticoid receptor, in patients with rheumatoid arthritis: a Phase 2 randomized study.[Pubmed:28328159]

Int J Rheum Dis. 2017 Aug;20(8):960-970.

AIM: To assess efficacy and safety of fosdagrocorat (PF-04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients. METHODS: This multicenter, double-blind, parallel-group, active- and placebo-controlled Phase 2 study (NCT00938587) randomized 86 patients (1 : 1 : 1 : 1) to receive fosdagrocorat 10 mg, fosdagrocorat 25 mg, prednisone 5 mg or placebo, all with stable background methotrexate therapy. The primary outcome was change from baseline in Disease Activity Score of 28 joints (DAS28-4[C-reactive protein (CRP)]) after 2 weeks of treatment. Secondary outcomes included American College of Rheumatology (ACR) response rates, change from baseline in ACR core components and Health Assessment Questionnaire Disability Index. RESULTS: At week 2, improvements from baseline in DAS28-4(CRP) with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo were -1.69, -2.22, -1.17 and -0.96, respectively, and were statistically significantly greater for both fosdagrocorat doses versus placebo (P < 0.05) and for fosdagrocorat 25 mg versus prednisone 5 mg (P < 0.001). The effects of fosdagrocorat on secondary outcomes were generally consistent with those observed for the primary outcome. Adverse events (AEs) were reported for eight (38%), three (14%), four (19%) and 12 (55%) patients treated with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo, respectively. Most AEs were mild in severity. Four patients discontinued treatment due to AEs (fosdagrocorat 10 mg, n = 2; placebo, n = 2). There were no serious AEs. CONCLUSION: Fosdagrocorat 10 and 25 mg demonstrated efficacy in improving signs and symptoms in RA patients, with manageable AEs. Additional studies are needed to assess the longer-term safety and efficacy of fosdagrocorat.

Clinical Activity of the gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis).[Pubmed:28350521]

J Clin Oncol. 2017 May 10;35(14):1561-1569.

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the gamma-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

Multireference configuration interaction study of the 27 low-lying states of the PF(+) cation.[Pubmed:28365453]

Spectrochim Acta A Mol Biomol Spectrosc. 2017 Jun 15;181:226-238.

This paper studied the spectroscopic parameters and vibrational properties of 27 Lambda-S and 60Omega states of PF(+) cation. The 27 Lambda-S states were the X(2)Pi, A(2)Sigma(+), B(2)Pi, C(2)Sigma(-), D(2)Delta, a(4)Sigma(-), b(4)Pi, c(4)Sigma(+), d(4)Delta, 2(2)Sigma(+), 3(2)Sigma(+), 4(2)Sigma(+), 2(2)Sigma(-), 3(2)Sigma(-), 3(2)Pi, 4(2)Pi, 5(2)Pi, 6(2)Pi, 2(2)Delta, 3(2)Delta, 1(2)Phi, 2(4)Sigma(-), 3(4)Sigma(-), 2(4)Pi, 3(4)Pi, 1(6)Sigma(-), and 1(6)Pi, which were generated from the first four dissociation limits. The 60Omega states were produced from the 27 Lambda-S states. All the potential energy curves were calculated with the CASSCF method, which was followed by the icMRCI+Q approach. The a(4)Sigma(-), b(4)Pi, and D(2)Delta states were inverted with the spin-orbit coupling effect accounted for. The 2(4)Pi, 2(4)Sigma(-), 2(2)Delta, 3(2)Delta, 3(2)Sigma(+), 4(2)Sigma(+), 1(2)Phi, and 2(2)Sigma(-) states were repulsive whether the spin-orbit coupling effect was included or not, but the 5(2)Pi and D(2)Delta states became repulsive only with the spin-orbit coupling effect included. The C(2)Sigma(-) state was very weakly bound. The a(4)Sigma(-) state had one barrier. The avoided crossings existed between the a(4)Sigma(-) and 2(4)Sigma(-) states, the 2(2)Sigma(+) and 3(2)Sigma(+) states as well as the D(2)Delta and 2(2)Delta states. Core-valence correlation and scalar relativistic corrections were taken into account. The extrapolation to the complete basis set limit was done. The spectroscopic parameters and vibrational properties were determined. The transition dipole moments were calculated and the Franck-Condon factors of some electric dipole transitions were evaluated. The spin-orbit coupling effect on the spectroscopic and vibrational properties was discussed.

Entrapment of DyP-type peroxidase from Pseudomonas fluorescens Pf-5 into Ca-alginate magnetic beads.[Pubmed:28326617]

Biotechnol Appl Biochem. 2018 Mar;65(2):238-245.

The aim of this study was to investigate the optimal conditions for the immobilization and stabilization of DyP1B dye decolorizing peroxidases type B (DyP1B) from Pseudomonas fluorescens Pf-5 immobilized in Ca-alginate ferromagnetic beads. The immobilized DyP1B was used in the degradation of the Reactive Blue 5 (RB5) synthetic dye. The enzyme was successfully entrapped in a Ca-alginate matrix and showed an encapsulation efficiency of 94%. The concentration of DyP1B (0.8 mg mL(-1) ), 2% of alginate and magnetite (10.0 mg mL(-1) ) was optimal for immobilization. The immobilized DyP1B showed optimum activity at pH 7.0 and 40 degrees C compared with pH 5.5 and 30 degrees C for free peroxidase. Reusability studies showed that after five cycles, the immobilized DyP1B system retained more than 58% of its initial activity. The immobilized DyP1B was able to decolorize RB5 at concentrations of 0.1, 0.05, and 0.01% (w v(-1) ) with efficiency rates of about 20, 29, and 45%, respectively. The immobilization of DyP1B in alginate beads with the addition of Fe3 O4 increased its catalytic and applicative potential.

Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay.[Pubmed:23098091]

J Med Chem. 2012 Nov 26;55(22):10047-63.

We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.