Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.

The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway.

1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. IPI-926 is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926 is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, IPI-926 has desirable pre-clinical absorption, distribution, metabolism and excretion properties.

A case of potential treatment of remote pain after sacral nerve stimulation for chronic urinary retention.

OBJECTIVE: A case is presented in which a 58-year-old man developed a potential unintended and durable treatment of pain at remote sites (cervical region and low back) after sacral nerve stimulation for chronic urinary retention. METHODS: Proper placement of the electrodes in the S3 foramen was confirmed by physiological response and fluoroscopy. RESULTS: Potential causality was shown by recurrent pain with the stimulators turned off and abatement of pain with the stimulators turned on. DISCUSSION: The current case presents a potential example of neurological crosstalk and highlights the inherent complexity in human neural physiology. Further research may reveal novel treatment strategies for patients with voiding dysfunction and chronic pain syndromes.

Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists.

Herein is reported the synthesis of a novel class of hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring of cyclopamine was homologated utilizing a sequence of chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification of the A/B-ring homoallylic alcohol to the conjugated ketone led to the discovery of new cyclopamine analogues with improved pharmaceutical properties and in vitro potency (EC 50) ranging from 10 to 1000 nM.

An additional antecedent of empathic concern: valuing the welfare of the person in need.

Two experiments examined the role of valuing the welfare of a person in need as an antecedent of empathic concern. Specifically, these experiments explored the relation of such valuing to a well-known antecedent--perspective taking. In Experiment 1, both perspective taking and valuing were manipulated, and each independently increased empathic concern, which, in turn, increased helping behavior. In Experiment 2, only valuing was manipulated. Manipulated valuing increased measured perspective taking and, in part as a result, increased empathic concern, which, in turn, increased helping. Valuing appears to be an important, largely overlooked, situational antecedent of feeling empathy for a person in need.

Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458.

OBJECTIVE: To determine the disease-modifying activity and mechanism of action of the orally available methionine aminopeptidase type 2 inhibitor, [(1R)-1-carbamoyl-2-methyl-propyl]-carbamic acid-(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro [2.5] oct-6-yl ester (PPI-2458), in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced arthritis. METHODS: Arthritis was induced in rats by administration of PG-PS, causing tarsal joint swelling and histopathologic changes characteristic of rheumatoid arthritis (RA). PPI-2458, a potent irreversible methionine aminopeptidase type 2 inhibitor, was administered orally every other day at 1, 5, or 10 mg/kg. RESULTS: In an in vitro osteoclastogenesis model, PPI-2458 potently inhibited osteoclast differentiation and bone resorption. In the rat PG-PS arthritis model, PPI-2458 afforded significant protection against established disease after therapeutic dosing. This in vivo activity of PPI-2458 was linked to the inhibition of methionine aminopeptidase type 2. Histopathologic assessment of affected joints showed improvement in processes of inflammation, bone resorption, and cartilage erosion, associated with significant improvement in all clinical indices. The protective effects of PPI-2458 against bone destruction in vivo, including the structural preservation of affected hind joints, correlated with improvements in bone histomorphometric markers, as determined by microfocal computed tomography and a significant decrease in systemic C-telopeptide of type I collagen, suggesting decreased osteoclast activity in vivo. Moreover, PPI-2458 prevented cartilage erosion as shown by a significant decrease in systemic cartilage oligomeric matrix protein. CONCLUSION: The findings of this study suggest that PPI-2458 exerts disease-modifying activity in experimental arthritis through its direct inhibition of several pathophysiologic processes of this disease. These results provide a rationale for assessing the potential of PPI-2458 as a novel RA therapy.

A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo.

PURPOSE: Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center-derived NHL cells. EXPERIMENTAL DESIGN: To examine the activity of PPI-2458 on germinal center morphology, spleen sections from cynomolgus monkeys treated with oral PPI-2458 were analyzed. Antiproliferative activity of PPI-2458 was assessed on germinal center-derived NHL lines in culture. A MetAP-2 pharmacodynamic assay was used to determine cellular MetAP-2 inhibition following PPI-2458 treatment. Finally, inhibition of MetAP-2 and proliferation by PPI-2458 was examined in the human SR NHL line in culture and in implanted xenografts. RESULTS: Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI(50) = 0.2-1.9 nmol/L) of several NHL lines in a manner that correlated with MetAP-2 inhibition. Moreover, orally administered PPI-2458 significantly inhibited SR tumor growth, which correlated with inhibition of tumor MetAP-2 (>85% at 100 mg/kg) in mice. CONCLUSIONS: These results show the potent antiproliferative activity of PPI-2458 on NHL lines in vitro and oral antitumor activity in vivo and suggest the therapeutic potential of PPI-2458 as a novel agent for treatment of NHL should be evaluated in the clinical setting.