Prognosis of Acute Kidney Injury and Hepatorenal Syndrome in Patients with Cirrhosis: A Prospective Cohort Study

Background/Aims. Acute kidney injury is a common problem for patients with cirrhosis and is associated with poor survival. We aimed to examine the association between type of acute kidney injury and 90-day mortality. Methods. Prospective cohort study at a major US liver transplant center. A nephrologist’s review of the urinary sediment was used in conjunction with the 2007 Ascites Club Criteria to stratify acute kidney injury into four groups: prerenal azotemia, hepatorenal syndrome, acute tubular necrosis, or other. Results. 120 participants with cirrhosis and acute kidney injury were analyzed. Ninety-day mortality was 14/40 (35%) with prerenal azotemia, 20/35 (57%) with hepatorenal syndrome, 21/36 (58%) with acute tubular necrosis, and 1/9 (11%) with other (p=0.04 overall). Mortality was the same in hepatorenal syndrome compared to acute tubular necrosis (p=0.99). Mortality was lower in prerenal azotemia compared to hepatorenal syndrome (p=0.05) and acute tubular necrosis (p=0.04). Ten participants (22%) were reclassified from hepatorenal syndrome to acute tubular necrosis because of granular casts on urinary sediment. Conclusions. Hepatorenal syndrome and acute tubular necrosis result in similar 90-day mortality. Review of urinary sediment may add important diagnostic information to this population. Multicenter studies are needed to validate these findings and better guide management

Structure Guided Optimization, In Vitro Activity and In Vivo Activity of Pan-PIM Kinase Inhibitors

Proviral Insertion of Moloney virus (PIM) 1, 2 and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. High expression of PIM1, 2 & 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias. As such, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts towards this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000 fold to yield compounds with pan PIM Ki’s < 10 picoM is described. During the optimization, a focus was initially placed on increasing potency while simultaneously reducing the liphophilicity and then, from a low logP space, a hydrophobic interaction was optimized. From these efforts, compound 5d was identified with suitable PK properties and kinase selectivity to establish a PK/PD-efficacy relationship in multiple myeloma and acute myeloid leukemia Pim dependent tumor models

Identification of N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1,2 and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

Pan Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2 and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model and pre-clinical profile of the potent and selective pan PIM kinase inhibitor 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor 1, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors

Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM <i>K</i>_is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described