Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production.

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,ß-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633).

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.

Ability of the finite element models to predict response of the human spine to sinusoidal vertical vibration.

STUDY DESIGN: The study examined the efficacy of the finite element models of various spinal segments in predicting the vibration response of the human spine. OBJECTIVE: To determine the optimal spinal segment finite element model to understand the effects of vibration on its biomechanics. SUMMARY OF BACKGROUND DATA: Several finite element models (one and two motion segments) have been proposed to look into the effects of vibration on the lumbar spine. However, they cannot be used to predict biomechanical parameters in the lumbar spine in response to whole body vibration. METHODS: A finite element model of the upper body from the head to the sacrum (H-S1) was generated. The H-=S1 model was altered to generate models of one motion segment (L3-L4), two motion segments (L3-L5), and the entire thoracolumbar spine and rib cage (T1-S1). The resonant frequencies of these models and effects of the trunk muscles and gravity were studied. RESULTS: The resonant frequencies decreased with the increase in the number of motion segments. However, the decrease plateaued beyond the T1-S1 segment model. The first resonant frequency in the vertical direction for the H-S1 model was 8.32 Hz. Inclusion of the trunk muscles and the preload of self-weight changed it to 8.91 and 6.82 Hz, respectively. CONCLUSIONS: Both the T1-S1 and H-S1 finite element models were able to predict vibration response of the human spine that closely matched in vivo experimental data reported in the literature.