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- Amrhein, JA, et al.
(författare)
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Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:23
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Tidskriftsartikel (refereegranskat)abstract
- The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N-myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d, which exhibited high cellular potency for CDK16 (EC50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20–120 nM and 50–180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2/M phase cell cycle arrest at all tested concentrations for 43d, caused by inhibition of CDK16.
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- Billeter, J., et al.
(författare)
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On decoupling rate processes in chemical reaction systems – Methods and applications
- 2018
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Ingår i: Computers and Chemical Engineering. - : Elsevier BV. - 0098-1354 .- 1873-4375. ; 114, s. 296-305
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Tidskriftsartikel (refereegranskat)abstract
- Models of chemical reaction systems can be complex as they need to include information regarding the reactions and the mass and heat transfers. The commonly used state variables, namely, concentrations and temperatures, express the interplay between many phenomena. As a consequence, each state variable is affected by several rate processes. On the other hand, it is well known that it is possible to partition the state space into a reaction invariant subspace and its orthogonal complement using a linear transformation involving the reaction stoichiometry. This paper uses a more sophisticated linear transformation to partition the state space into various subspaces, each one linked to a single rate process such as a particular reaction, mass transfer or heat transfer. The implications of this partitioning are discussed with respect to several applications related to data reconciliation, state and rate estimation, modeling, identification, control and optimization of reaction systems.
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- Rodrigues, Diogo, et al.
(författare)
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Fast Estimation of Plant Steady State for Imperfectly Known Dynamic Systems, with Application to Real-Time Optimization
- 2018
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Ingår i: Industrial & Engineering Chemistry Research. - : American Chemical Society (ACS). - 0888-5885 .- 1520-5045. ; 57:10, s. 3699-3716
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Tidskriftsartikel (refereegranskat)abstract
- Experimental assessment or prediction of plant steady state is important for many applications in the area of modeling and operation of continuous processes. For example, the iterative implementation of static real-time optimization requires reaching steady state for each successive operating point, which may be quite time-consuming. This paper presents an approach to speed up the estimation of plant steady state for imperfectly known dynamic systems that are characterized by (i) the presence of fast and slow states, with no effect of the slow states on the fast states, and (ii) the fact that the unknown part of the dynamics depends only on the fast states. The proposed approach takes advantage of measurement-based rate estimation, which consists in estimating rate signals without the knowledge or identification of rate models. Since one can use feedback control to speed up the convergence to steady state of the fast part of the plant, this rate estimation allows estimating the steady state of the slow part during transient operation. It is shown how this approach can be used to speed up the static real-time optimization of continuous processes. A simulated example illustrates its application to a continuous stirred-tank reactor.
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