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Blog of Signaling Pathways

NTRK fusion-positive cancers and TRK inhibitor therapy

0 views | Apr 05 2020

Cocco E D et al. discussed the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors. [Read the Full Post]

BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines

0 views | Apr 05 2020

Blume T et al. suggested that carefully dosed inhibitors might be therapeutically effective without affecting the structural integrity of excitatory synapses if given at an early disease stage. [Read the Full Post]

Rapamycin combined with MCC950 to treat multiple sclerosis in experimental autoimmune encephalomyelitis

0 views | Apr 01 2020

Xu L et al. provided theoretical support to the therapeutic evaluation of RAPA and MCC950 to make the mammalian targets of RAPA and NLRP3 the therapeutic targets of MS. [Read the Full Post]

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

0 views | Apr 01 2020

Cervantes-Madrid D et al. showed that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of neuroblastoma. [Read the Full Post]

Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer

2 views | Mar 31 2020

Molina-Arcas M et al. provided a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials. [Read the Full Post]

Effects of the Preparation Method on the Formation of True Nimodipine SBE-β-CD/HP-β-CD Inclusion Complexes and Their Dissolution Rates Enhancement

0 views | Mar 31 2020

Semcheddine F et al. showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products. [Read the Full Post]

Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery

0 views | Mar 30 2020

Colclough N et al. demonstrated how these innovative kinase inhibitors were recognized as brain penetrant and outline our view of experimental approaches and strategies that can facilitate the discovery of new brain-penetrant therapies for the treatment of primary and secondary CNS malignancies as well as other CNS disorders. [Read the Full Post]

AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK

3 views | Mar 30 2020

Yadav AK et al. demonstrated that AZD1208 inhibits growth of liposarcoma cells and that this activity is mediated through Pim-3 kinase, STAT-3, mTOR, S6 and AMPK expression and phosphorylation pathways. [Read the Full Post]

Multiple myeloma with 1q21 amplification is highly sensitive to MCL-1 targeting

0 views | Mar 29 2020

Slomp A et al. indicated that amplification of 1q21 identifies an MM subset highly sensitive to MCL-1 inhibitor treatment and can be used as a predictive marker to guide selection of therapy. [Read the Full Post]

Real-World Data of Triplet Combination of Trastuzumab, Lapatinib, and Chemotherapy in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study

4 views | Mar 29 2020

Li Y et al. indicated that TLC demonstrated promising effects and tolerable safety in HER2+MBC, even in patients with BM, providing a theoretical basis for clinical practice. [Read the Full Post]

Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor

4 views | Mar 26 2020

Gu Y et al. supported clinical development of savolitinib. Understanding the preclinical PK/PD relationship of savolitinib provides translational insights into the cMet-targeted drug development. [Read the Full Post]

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

6 views | Mar 26 2020

Augello G et al. indicated their results offer hope for a new therapeutic opportunity in the treatment of HCC patients. [Read the Full Post]

TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer

6 views | Mar 25 2020

Zhao B et al. showed accumulation of MEKi in the lysosomes of treated cells. [Read the Full Post]

Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia

3 views | Mar 24 2020

Serafin V et al. suggested a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients. [Read the Full Post]

Bcl-2high mantle cell lymphoma cells are sensitized to acadesine with ABT-199

4 views | Mar 23 2020

Montraveta A et al. supported the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients. [Read the Full Post]

NTRK fusion-positive cancers and TRK inhibitor therapy

10 views | Mar 23 2020

Cocco E et al. discussed the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors. [Read the Full Post]

Small molecule inhibitor RepSox prevented ovariectomy-induced osteoporosis by suppressing osteoclast differentiation and bone resorption

7 views | Mar 22 2020

Mei L et al. suggested that RepSox regulates osteoclast differentiation, bone resorption, and OVX-induced OP via the suppression of the Smad3 and JNK/AP-1 pathways. [Read the Full Post]

Biguanides Induce Acute de novo Lipogenesis in Human Primary Sebocytes

3 views | Mar 22 2020

Nicoll J et al. found that biguanides, isotretinoin and azithromycin induced an acute dose and time-dependent increase in [14C]-acetate labeling of neutral lipids, while AICAR, an AMPK activator, inhibited this DNL response. Biguanides did not activate AMPK in sebocytes, however, they significantly reduced oxygen consumption rate and increased lactate production. Treatment with biguanides, but not isotretinoin, significantly upregulated ACSS2 gene expression in primary sebocytes and showed synergism with lipogenic activators to induce DNL genes. [Read the Full Post]

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice

9 views | Mar 21 2020

Parikh SA et al. illustrated the challenges associated with continuous oral therapy with ibrutinib in patients with CLL. [Read the Full Post]

Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL

3 views | Mar 21 2020

Rendeiro AF et al. described time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring. [Read the Full Post]