37 research outputs found
Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold
No full textSLK
(STE20-like kinase) and STK10 (serine/threonine kinase 10)
are closely related kinases whose enzymatic activity is linked to
the regulation of ezrin, radixin, and moesin function and to the regulation
of lymphocyte migration and the cell cycle. We identified a series
of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10
with good kinome-wide selectivity. Optimization of this series led
to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures
of exemplar inhibitors bound to SLK and STK10 demonstrated the binding
mode of the inhibitors and rationalized their selectivity. Cellular
target engagement assays demonstrated the binding of the inhibitors
to SLK and STK10 in cells. Further selectivity analyses, including
analysis of activity of the reported inhibitors against off-targets
in cells, identified compound 31 as the most potent and
selective inhibitor of SLK and STK10 yet reported
Discovery of a potent dual SLK/STK10 inhibitor based on a maleimide scaffold
No full textSLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported
Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold
No full textSLK
(STE20-like kinase) and STK10 (serine/threonine kinase 10)
are closely related kinases whose enzymatic activity is linked to
the regulation of ezrin, radixin, and moesin function and to the regulation
of lymphocyte migration and the cell cycle. We identified a series
of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10
with good kinome-wide selectivity. Optimization of this series led
to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures
of exemplar inhibitors bound to SLK and STK10 demonstrated the binding
mode of the inhibitors and rationalized their selectivity. Cellular
target engagement assays demonstrated the binding of the inhibitors
to SLK and STK10 in cells. Further selectivity analyses, including
analysis of activity of the reported inhibitors against off-targets
in cells, identified compound 31 as the most potent and
selective inhibitor of SLK and STK10 yet reported
Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold
No full textSLK
(STE20-like kinase) and STK10 (serine/threonine kinase 10)
are closely related kinases whose enzymatic activity is linked to
the regulation of ezrin, radixin, and moesin function and to the regulation
of lymphocyte migration and the cell cycle. We identified a series
of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10
with good kinome-wide selectivity. Optimization of this series led
to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures
of exemplar inhibitors bound to SLK and STK10 demonstrated the binding
mode of the inhibitors and rationalized their selectivity. Cellular
target engagement assays demonstrated the binding of the inhibitors
to SLK and STK10 in cells. Further selectivity analyses, including
analysis of activity of the reported inhibitors against off-targets
in cells, identified compound 31 as the most potent and
selective inhibitor of SLK and STK10 yet reported
Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold
No full textSLK
(STE20-like kinase) and STK10 (serine/threonine kinase 10)
are closely related kinases whose enzymatic activity is linked to
the regulation of ezrin, radixin, and moesin function and to the regulation
of lymphocyte migration and the cell cycle. We identified a series
of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10
with good kinome-wide selectivity. Optimization of this series led
to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures
of exemplar inhibitors bound to SLK and STK10 demonstrated the binding
mode of the inhibitors and rationalized their selectivity. Cellular
target engagement assays demonstrated the binding of the inhibitors
to SLK and STK10 in cells. Further selectivity analyses, including
analysis of activity of the reported inhibitors against off-targets
in cells, identified compound 31 as the most potent and
selective inhibitor of SLK and STK10 yet reported
An argument for expanding the simultaneous liver and kidney transplant criteria: Validity of the new UNOS allocation policy.
No full textAim: According to the latest simultaneous liver-kidney transplant (SLK) allocation policy by UNOS, allocation of kidney is dependent on duration of low glomerular filtration rate (GFR) (Chronic kidney disease [CKD] criteria: GFR/min for \u3e90 days and/min at registration) or sustained acute kidney injury (AKI criteria; duration of dialysis \u3e6 weeks). Our practice has been to utilize SLK for patients who required dialysis longer than 4 weeks or those who had CKD not associated with hepatorenal syndrome. We aimed to review our indications of SLK, compare outcomes between SLK and liver transplant alone (LTA) in patients with renal dysfunction, and assess validity of the new UNOS SLK policy.
Methods: We retrospectively reviewed 532 primary deceased donor LT patients from 2009 to 2015. SLK patients and LTA patients who met the new CKD criteria were evaluated. Graft survival, post-transplant dialysis requirement, and recovery of kidney function were set as endpoints and compared between the groups.
Results: 44 patients underwent SLK, of whom 21 met the AKI criteria while 17 met the CKD criteria. Six SLK patients (14%) did not meet either of the AKI or CKD criteria. 72 patients with GFR \u3c30mL/min underwent LTA; of whom 27 met the CKD criteria (LTA-CKD group). The new UNOS SLK criteria would have increased SLK by 47% (44 to 65 cases, [44-6+27]/44=1.47) and raised it in the entire liver transplant cohort by 4% (21/532). The LTA-CKD group showed worse one-year graft survival rate, compared with the SLK group (81% vs. 93%, P=0.15). Post-transplant dialysis was required more frequently in the LTA-CKD group than the SLK (59% vs. 27%, P=0.01). Post-transplant GFR at 3, 6, and 12 months was significantly worse in the LTA-CKD group than the SLK group (46 vs. 78mL/min at 3 months [P\u3c0.001], 49 vs. 70mL/min at 6 months [P\u3c0.001], and 46 vs. 69mL/min at 12 months [P=0.02]). Conditional graft survival after one year was similar (P=0.8).
Conclusion: The new UNOS SLK allocation criteria will significantly increase the number of SLK\u27s, decrease the risk of post-transplant dialysis, and potentially improve short-term outcomes in patients with marginal kidney function
Impact on Waitlist Outcomes from Changes in the Medical Eligibility of Candidates for Simultaneous Liver-Kidney Transplantation Following Implementation of the 2017 Organ Procurement and Transplantation Network/United Network for Organ Sharing Policy in the United States
No full textBACKGROUND: The new simultaneous liver-kidney transplantation (SLK) listing criteria in the United States was implemented in 2017. We aimed to investigate the impact on waitlist and post-transplantation outcomes from changes in the medical eligibility of candidates for SLK after policy implementation in the United States.
MATERIAL AND METHODS: We analyzed adult primary SLK candidates between January 2015 and March 2019 using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) registry. We compared waitlist practice, post-transplantation outcomes, and final transplant graft type in SLK candidates before and after the policy.
RESULTS: A total of 4641 patients were eligible, with 2975 and 1666 registered before and after the 2017 policy, respectively. The daily number of SLK candidates was lower after the 2017 policy (3.25 vs 2.89, P=0.01); 1956 received SLK and 95 received liver transplant alone (LTA). The proportion of patients who eventually received LTA was higher after the 2017 policy (7.9% vs 3.0%; P\u3c0.001). The 1-year graft survival rate was worse in patients with LTA than in those with SLK (80.5% vs 90.4%; P=0.003). The adjusted risk of 1-year graft failure in patients with LTA was 2.01 (95% confidence interval 1.13-3.58, P=0.01) compared with patients with SLK among the SLK candidates.
CONCLUSIONS: Although the number of registrations for SLK increased, the number of SLK transplants decreased, and the number of liver transplants increased. LTA in this patient cohort was associated with worse post-transplantation outcomes
Rapid deterioration of pre-transplant kidney function requiring dialysis is a prognostic factor in liver transplant alone
No full textAim: Etiologies of acute kidney injury before liver transplant extend beyond hepatorenal syndrome (ie infection, gastrointestinal bleeding) and therefore, may not be resolved by liver transplantation. We hypothesized that rapid deterioration of kidney function immediately before transplant would impact outcome significantly. The aim of this study was to review the safety of liver transplant alone (LTA) in cases of rapid deterioration of kidney function requiring dialysis by comparing outcomes in liver transplant alone (LTA) and simultaneous liver-kidney transplant (SLK).
Methods: We retrospectively reviewed of 532 primary deceased donor LT patients from 2009 to 2015. SLK patients (n=44) were compared to patients who required pre-transplant dialysis. The latter group was categorized according to the duration of low GFR (Group 1: GFR\u3c30mL/min for 3 weeks or less [rapid deterioration group, n=24], Group 2: GFR\u3c30mL/min over 3 weeks [sustained injury group, n=16]).
Results: Median durations of low GFR (\u3c60mL/min and \u3c30mL/min) and pretransplant dialysis were shorter in Group 1 than Group 2 (23, 13, and 7 days vs. 51, 33, and 18 days). Group 1 showed significantly worse one-year survival than the SLK group (66% vs. 93%, P=0.01), whereas it was comparable between the Group 2 and SLK group (88% vs. 93%, P=0.52). Post-transplant dialysis was required in 100% and 87% of patients in Groups 1 and 2, respectively. Seven patients in Group 1 died in the first year, five of whom remained on dialysis until their deaths. In Group 2, one patient who recovered kidney function died of PTLD on POD 220. While GFR at 12 months after transplant was significant better in the SLK group, it was comparable between Groups 1 and 2, (63, 47, and 45mL/min in the SLK, Groups 1, and 2, respectively, P=0.03). Graft survival after one year was similar among these 3 groups (P=1.0).
Conclusion: Rapid deterioration of kidney function before LTA, rather than sustained kidney injury, is more likely lead to persistent renal failure and increase one-year mortality. In patients with rapid renal dysfunction; deferring LTA until etiology of renal dysfunction can be clarified may be warranted. Further investigation is needed determine if SLK improves early outcomes of this population
Liver alone or simultaneous liver-kidney transplant? Pretransplant chronic kidney disease and post-transplant outcome - a retrospective study
No full textThe new Organ Procurement and Transplant Network/United Organ Sharing Network (OPTN/UNOS) simultaneous liver-kidney transplant (SLK) policy has been implemented. The aim of this study was to review liver transplant outcomes utilizing the new SLK policy. Liver transplant alone (LTA) and SLK patients between 2009 and 2015 were reviewed. Graft survival and post-transplant kidney function were investigated among LTA patients meeting the chronic kidney disease (CKD) criteria of the new policy (LTA-CKD group). To validate our findings, we reviewed and applied our analysis to the OPTN/UNOS registry. A total of 535 patients were eligible from our series. The LTA-CKD group (n = 27) showed worse 1-year graft survival, compared with the SLK group (n = 44), but not significant (81% vs. 93%, P = 0.15). The LTA-CKD group significantly increased a risk of post-transplant dialysis (odds ratio = 5.59 [95% CI = 1.27-24.7], P = 0.02 [Ref. normal kidney function]). Post-transplant dialysis was an independent risk factor for graft loss (hazard ratio = 7.25, 95% CI = 3.3-15.91, P \u3c 0.001 [Ref. SLK]). In the validation analysis based on the OPTN/UNOS registry, the hazard of 1-year-graft loss in the LTA-CKD group (n = 751) was 34.8% higher than the SLK group (n = 2856) (hazard ratio = 1.348, 95% CI = 1.157-1.572, P \u3c 0.001). Indicating SLK for patients who meet the CKD criteria may significantly improve transplant outcomes
FATE OF LIVER AND KIDNEY TRANSPLANT CANDIDATES BEFORE AND AFTER SIMULTANEOUS LIVER-KIDNEY TRANSPLANT ALLOCATION POLICY CHANGE
No full textBackground: The OPTN/UNOS policy for kidney allocation to liver transplant (LT) recipients was implemented on August 10th, 2017. We investigated the impact of the policy change on outcomes on simultaneous liver-kidney transplantation (SLK) candidates.
Methods: Using OPTN/UNOS data, we analyzed adult SLK candidates between January 2015 and March 2019. We excluded patients registered for retransplant. Patients were classified into two cohorts; cohort 1: from January 1st, 2015 to July 31st, 2017 (pre-policy group), cohort 2: from September 1st, 2017 to March 30th, 2019 (post-policy group). Waitlist outcomes, including 90-day mortality, transplant probability, and type of transplant (SLK vs. LT alone [LTA]) were compared between the two cohorts using a Fine-Gray competing risk regression model. Post-transplant outcomes were compared according to transplant type using a Cox regression model.
Results: Of the 4641 patients eligible for this study, 2975 and 1666 were registered in cohorts 1 and 2, respectively. The average number of waitlisted patients (daily) was significantly lower in cohort 2 compared to cohort 1 (2.89/day vs. 3.25/day; p=0.013). In patients with MELD score \u3e35, there was significantly higher 90-day transplant probability in cohort 2 (adjusted hazard ratio [aHR]:1.23, p=0.032); whereas no significant difference was observed in patients with MELD scores 30-34 or \u3c29. The patients in cohort 2 with MELD scores ≥35 trended towards a lower 90- day waitlist mortality compared to patients in cohort 1 (aHR: 0.69, p=0.06). Regarding transplant type, the proportion of LTA in SLK candidates was significantly higher in cohort 2 compared to cohort 1; both overall (7.9% vs. 3.0%, P\u3c0.001) and when stratified by MELD score (≤29, 30-34, ≥35; p=0.006, 0.008, 0.004, respectively) (Figure 1). Adjusted risk of 1-year graft loss was significantly higher in LTA compared to SLK (aHR 2.01, p=0.012) (Figure 2).
Conclusion: The new SLK policy significantly decreased the number of SLK transplants while significantly improving waitlist outcomes, especially in patients with higher MELD scores. After the policy change, patients who were initially registered for SLK more frequently received LTA, likely due to more stringent criteria. Because LTA outcomes were significantly worse than SLK in SLK candidates, the decision on transplant type for this patient population needs careful assessment
