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Treatments and Challenges
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Despite their targeted activity, multiple mechanisms of feedback inhibition and kinase crosstalk exist in almost every kinase-signaling network. In cancer treatment, adaptations of the kinome (i.e., protein kinase superfamily) may eventually lead to treatment failure [1169–1171]. Studies report that tumor cells hijack pathway redundancy and feedback routes, as well as crosstalk, by adapting cellular signaling circuitry as a response to chronic drug treatment to maintain their functions and survival [1169]. Hence, small-molecule inhibitor drugs targeting receptor tyrosine kinases when used as single agents cause tumor shrinkage, but not complete elimination [1170]. The lingering tumor cells (i.e., residual disease) can act as the platform from which acquired treatment resistance emerges [1170]. Acquired resistance to kinase inhibitors often occurs and most patients eventually relapse [1172]. Resistance follows either from an adaptive multifactorial process, where signaling pathways are remodeled to relieve the effects of (kinase) inhibition, or from longer-term processes (i.e., gradual adaptation), where tumor cells acquire mutations or gene copy number modifications that bestow a selective advantage (i.e., inhibitor-specific selective pressures) to mitigate the negative effects of treatment [374, 1172, 1173]. There are other published reviews that provide detailed information on kinase inhibitors, and the reader is referred to these reviews [1174–1177].
“Omics” Technologies in Vaccine Research
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
A detailed picture of the protein-to-protein interactions related to the immune responses against infections, virulence of the pathogen, or host-pathogen interactions can be obtained via proteomics, and “interactome” of the cell is revealed. Proteins undergo modifications to gain their function or they are found in different locations of the cell. These certain groups of proteins can be isolated and identified using proteomics techniques. For instance, phosphorylated proteins playing roles in the signal transduction are identified via the phosphoproteomics technique, and the “kinome” of the cell is identified (Buonaguro and Pulendran 2011) or secreted proteins can be identified via “secretome” analysis (Bidmos et al. 2018).
The Cardiovascular System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Calvert Louden, David Brott, Chidozie J. Amuzie, Bindu Bennet, Ronnie Chamanza
The success of targeting TKs, particularly TK inhibitors, as life-saving cancer therapies, has prompted the need for a better understanding of the MOA associated with cardiotoxicity to significantly improve on the nonclinical to clinical translation (Zhang et al. 2009). Developing a clear picture of the important signaling pathways for members of the kinome for therapeutic target selection, and secondary pharmacology screening to improve the safety profile for cardiotoxicity, is a major hurdle. Because kinases are important regulatory proteins that act through a vast, interconnected network of cellular processes, toxicity can arise from intended or unintended “bystander” targets that have no role in the desired biologic effect, e.g., tumorigenesis. Determining which of these off target kinases play a role in the maintenance of normal cardiac physiology and function will aid in selection of pharmacologically active targets and/or molecules with a low risk for cardiotoxicity. Identification of these signaling pathways will enable development and utilization of secondary pharmacology screens in nonclinical toxicology studies and this investment could reduce attrition significantly. It is clear that TK-induced cardiotoxicity is not a class effect, because targeting kinase inhibitors of the epidermal growth factor receptor (EGFR) family does not seem to cause cardiotoxicity (Force et al. 2007). Therefore, potential cardiotoxicity of novel emerging targets of TK inhibition must be assessed on a case-by-case basis (Force et al. 2007).
Parasite and host kinases as targets for antimalarials
Published in Expert Opinion on Therapeutic Targets, 2023
Han Wee Ong, Jack Adderley, Andrew B. Tobin, David H. Drewry, Christian Doerig
When attempting to uncover the mode of action of kinase inhibitors scaffolds that display parasiticidal activity in vitro but whose target(s) is/are unknown, one must keep in mind that targets may be present in both the parasite and the host erythrocyte. Several host kinases have been implicated in infection at both the blood and the liver stages, and pharmacological [175] or reverse genetics [176] interference with several host kinases does impair parasite survival. A promising aspect of host-directed therapy (HDT) is that drugs that target an enzyme of the host cell (rather than the pathogen) are less susceptible to the emergence of resistance because mutations in the target that confer resistance cannot be selected by drug pressure if the target is not under the pathogen’s genetic control. Indeed, preliminary experiments (Adderley and Doerig, unpublished) suggest that highly selective inhibitors of host erythrocyte kinases are largely refractory to the emergence of resistance in in vitro selection experiments. Of particular interest are kinases belonging to groups that are absent from the parasite’s kinome, such as Tyrosine Kinases. To illustrate the avenues that are being opened by such a strategy, it is of interest to cite a recent study showing that co-administering Imatinib (a well-tolerated Tyrosine Kinase inhibitor initially developed for the treatment of leukemia) with standard artemisinin combinations led to a significantly accelerated decline in parasite density in treated patients without added toxicity [177].
A patent and literature review of CDK12 inhibitors
Published in Expert Opinion on Therapeutic Patents, 2022
Ruijun Tang, Jing Liu, Shuyao Li, Junjie Zhang, Chunhong Yu, Honglu Liu, Fang Chen, Lu Lv, Qian Zhang, Kai Yuan, Hao Shao
The Gray group reported the first CDK12-specific degrader 22 (BSJ-4-116, Figure 4) [54,55]. The starting point for BSJ-4-116 was the dual CDK12/13 covalent inhibitor THZ531. A series of degrader molecules were synthesized and screened by western blotting identified 30 (BSJ-4-23, Figure 4) as a potent CDK12 degrader. Compound 30 degraded CDK12 at 250 nM in Jurkat cells, while sparing CDK13 at the same concentration. Replacing the 4-(piperazin-1-yl)aniline with (R)-3-aminopiperidine from a promiscuous multi-kinase degrader molecule 23 (TL12-186, Figure 4) resulted in 22 (BSJ-4-116, Figure 4). Similarly, 22 inhibited CDK12 enzymatic activity with a low nanomolar IC50 and degraded CDK12 in Jurkat cells in a dose- and time-dependent manner without affecting CDK13. It exhibited a highly selective kinome profile, evidenced by a KINOMEscan profiling against a panel of 468 human kinases at 1 μM. The compound was also selective at protein degradation and CDK12 turned out to be the only kinase that was significantly reduced in a proteome-wide proteomic profiling. 22 downregulated the expression of DDR genes and exhibited antiproliferative activity in cancer cells. 22 also substantially suppressed the phosphorylation of Pol II Ser2 and Thr4, while not inhibiting p-Ser5 and p-Ser7. Moreover, 22 exhibited potent antiproliferative activities, alone and in combination with the PARP inhibitor Olaparib.
The pre-clinical discovery and development of osimertinib used to treat non-small cell lung cancer
Published in Expert Opinion on Drug Discovery, 2021
Florian Wittlinger, Stefan A. Laufer
For in vivo proof of concept examinations, 6 was further evaluated showing encouraging antiproliferative effects (EC50: PC9 = 0.14 µM, H1975 = 0.099 µM, and LoVo = 1.78 µM). Follow-up oral applications as mesylate salt formulation in PC9-/H1975-/A431 (wt) xenograft models in immune compromised mice were also promising (stated as tumor growth inhibition (TGI) with 134%, 105%, and 46%, respectively). Furthermore, kinome selectivity was tested on a panel of > 70 diverse kinases at 1 µM in an enzymatic assay. Other ten kinases were hit with > 75% inhibition: IGF1R, insulin receptor, CAMKKbeta, CHK2, PBK, FLT1, MAP3K11, smMLCK, BTK, and MELK, whereof only BTK has a cysteine at the same location as EGFR. Unfortunately, 6 possessed poor solubility (1.6 µM) and an IC50 of 4.2 µM for human Ether-à-go-go-Related Gene (hERG), which is associated with QT prolongation and cardiac adverse effects when potently hit by drugs [77,78].