P1, N=25, Recruiting, DeuterOncology | Trial completion date: Apr 2025 --> Dec 2026 | Trial primary completion date: Oct 2024 --> Dec 2025

P1, N=54, Recruiting, PharmaEngine | Not yet recruiting --> Recruiting | Trial completion date: Dec 2026 --> Aug 2027 | Trial primary completion date: Jul 2026 --> Feb 2027

The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant. ER121 is a non-toxic small-molecule erbB kinase inhibitor and holds promise as an oral and systemic therapeutic agent for treating progressive erbB-driven tumors in therapeutic settings. Moreover, ER121 shows potential as a preventive therapy in neoadjuvant settings for erbB2-associated tumors and when administered systemically can dramatically limit erbB2 brain metastases in animal models.

The lead compound 2D7 (a.k.a. eCCA352) induces pan-OC activity and cell cycle arrest in the submicromolar range and was determined to inhibit Aurora kinase A, providing a new starting point to develop anticancer targeted agents against OC.

4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski's rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.

No abstract available

The current state of knowledge on ALK inhibitors used in clinical practice is summarised in this research paper. Methods of diagnosis of abnormalities in ALK have been shown, and the review of research that contributed to the development of the next generation of ALK inhibitors has been presented.

We regarded ABL1, EGFR, and LCK as on-target kinases; among the two corresponding on-target kinase inhibitors, osimertinib and ponatinib emerged as on-target drugs whose target kinases were significantly activated. The remaining 26 kinases and seven kinase inhibitors were excluded as off-targets. Our pharmacoproteomic approach enabled the identification of on-target kinase inhibitors that are useful for drug repositioning.

Aim: We conducted network meta-analysis to assess cardiovascular toxicity of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs).Materials & Eleven articles involving 2855 patients and six interventions including crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and chemotherapy were analyzed. No significant difference was observed in overall cardiovascular risk among ALK-TKIs. For vascular toxicity, crizotinib and ceritinib had a higher risk of thrombotic events than brigatinib. Crizotinib and lorlatinib were more likely to cause blood pressure abnormalities. Clinicians should carefully monitoring cardiovascular events when ALK-TKIs used in NSCLCs patients with baseline cardiovascular diseases.

Combination kinase inhibitors with immunotherapy as first-line therapy are safe and effective for the treatment of unresectable ATC, especially with BRAF V600E mutation.

These results underscore the pivotal role of CERK inhibition in bolstering OAcGD2 synthesis, thus, presenting a promising strategy to increase the efficacy of anti-OAcGD2-based immunotherapy in patients with neuroectodermal tumors. By shedding light on this intricate interplay, our study paves the way for innovative therapeutic strategies poised to revolutionize the treatment landscape for these aggressive malignancies.

The three promising anti-proliferative hybrids (1a, 8a, 13a) were selected for the assessment of their in vitro inhibitory kinase activity against CDK2/GSK3β using roscovitine (IC50 = 0.88 μg mL-1) and CHIR-99021 (IC50 = 0.07 μg mL-1) as references, respectively...Moreover, it resulted in an increase in Bax and caspase-3 with a decrease in Bcl-2 levels in HepG2 cells compared with untreated cells. Finally, in silico drug likeness/ADME prediction for the three potent compounds as well as a molecular docking simulation study were conducted in order to explore the binding affinity and interactions in the binding site of each enzyme, which inspired their usage as anti-proliferative leads for further modification.

Additionally, the binding affinity, residence time, and even JNK isoform specificity can be fine-tuned by adjusting the substitution pattern or using divergent and orthogonal synthetic elaboration of the warhead. Taken together, the cyclic warheads presented in this study will be a useful tool for medicinal chemists for the deliberate design of safer and functionally fine-tuned covalent inhibitors.

Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

P1, N=79, Completed, Royal Marsden NHS Foundation Trust | Unknown status --> Completed

Molecular simulation studies revealed Dabrafenib's thermodynamically stable interactions (ΔG), tighter binding, and less structural deviation in the order EGFR > HER-2 > ER > PR as compared to Palbociclib (HER-2 > ER > PR = EGFR). These results indicate that Dabrafenib, compared to Palbociclib, more effectively regulates breast cancer cell proliferation through specific interactions with hormonal and growth factor receptors towards a repurposing approach.

This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cpKa without recourse to intramolecular hydrogen bonds.

P2, N=115, Active, not recruiting, Fudan University | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

A few small chemical inhibitors (E.g., SGI-1776, AZD1208, LGH447) that specifically target the PIM proteins' adenosine triphosphate (ATP)-binding domain have been identified. We explore the involvement of oncogenic transcription factor c-Mycandmi-RNA in relation to PIM kinase. In this article, we highlight the oncogenic effects, and structural insights into PIM kinase inhibitors for the treatment of cancer.

Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compounds 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.

ICIs may significantly benefit PFS among patients with EGFR-mutated NSCLC who have progressed on TKI treatment. Future research should continue stratifying patients based on prior treatment exposure to optimize therapeutic strategies.

Our patient experienced clinical benefit from first and second generation ALK inhibition in a chemotherapy refractory tumor. Tumor mutation profiling can identify mutations that may render tumors sensitive to targeted therapy with tyrosine kinase inhibitors.

P1, N=7, Terminated, Cyclacel Pharmaceuticals, Inc. | N=50 --> 7 | Recruiting --> Terminated; Switch to oral formulation of CYC140 (plogosertib)

Furthermore, our investigation reveals that reactive cysteine residues are highly conserved across the Kinase Inhibitory Domain (KID) sequences of p21 proteins from higher eukaryotes, and the p27 and p57 human paralogs. We propose that the presence of conserved regulatory cysteines within the KIDs of p21 family members from multiple taxa provides those proteins with the capability for directly sensing ROS, enabling the direct regulation of cyclin kinase activity by ROS levels.

The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.

Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways.

Interestingly, cytotoxic investigation of this compound revealed potential activity against the tested cancer cell lines (Caco-2, MCF7 and HepG2) with IC50 values of 6.2, 8.5 and 9.3 µg/ml, respectively. The present study highlighted the potential of G. segetum Ker-Gawl as a promising source of interesting anticancer scaffolds.

These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

(Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).

It concluded that mitochondria-derived ROS mediated differentiation of PECs into podocytes via Nrf2 and Brg1 signaling.

Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

Its enhancement of ALA-PDT was largely due to the increase of intracellular PpIX particularly in the mitochondria, resulting in the activation of mitochondria-mediated apoptosis in H4 cells. Our present study demonstrates that lapatinib inhibits ABCG2-mediated PpIX efflux and sensitizes GBM cells to ALA-PDT by inducing tumor cell death.

The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib...Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.

P2, N=120, Not yet recruiting, Hamilton Health Sciences Corporation | Initiation date: Apr 2024 --> Oct 2024

These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC.

P2, N=49, Terminated, Boehringer Ingelheim | Trial completion date: Mar 2025 --> Aug 2024 | Active, not recruiting --> Terminated; Company decision

P1, N=48, Terminated, Boehringer Ingelheim | Trial completion date: Oct 2025 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Oct 2025 --> Aug 2024; Company decision

For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines.

PLR and TC were potential clinical predictive factors for survival outcomes in patients with advanced HCC who received ICI/kinase inhibitor combination therapy. It is important to know the clinical characteristics of patients prior to treatment initiation to optimize outcomes.

As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs.

Examination of their electronic structure via density functional theory revealed efficient properties, with the highest occupied molecular orbital-least unoccupied molecular orbital energy gap values ranging from -3.984 eV to -6.547 eV. Further, in vivo analysis is required to gain a more comprehensive understanding and efficacy of these identified phytochemicals against lung cancer.