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CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Treatment options for CLOVES syndrome and other PIK3CA-related overgrowth disorders include surgical debulking (for truncal lipomatous mass), orthopedic care (for scoliosis/kyphosis and leg-length discrepancy), neurosurgical intervention (for obstructive hydrocephalus, increased intracranial pressure, progressive/symptomatic cerebellar tonsillar ectopia, Chiari malformation, and epilepsy), and other procedures (for cardiac and renal abnormalities; intellectual disabilities, behavior problems, motor difficulties, speech, swallowing, and feeding difficulties). Use of PI3K inhibitor (pictilisib, copanlisib, duvelisib), Akt inhibitor (ipatasertib, MK-2206, ARQ-092), mTOR inhibitor (rapamycin), and dual PI3K/AKT/mTOR inhibitor (gedatolisib, apitolisib) offers another approach for management of PIK3CA-related overgrowth spectrum [25].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There are three examples of allosteric inhibitors which exploit the specificity of the Akt isozyme to bind to its allosteric site where a pocket exists at the interface of the catalytically active kinase and PH domains which locks Akt into a “closed” conformation which cannot be activated by PDK1, thus inhibiting Akt activation. Through this mechanism, allosteric inhibitors can show selectivity between the different Akt subtypes. Developed by Merck & Co, MK-2206 was the first allosteric Akt inhibitor to enter clinical trials for the evaluation of activity in breast cancer. It is a highly selective pan-AKT inhibitor of all three AKT isoforms (AKT 1, AKT 2, and AKT 3), and was originally evaluated as a monotherapy for the treatment of AML. It has also been evaluated in Phase II clinical trials in advanced non-small-cell lung carcinoma in combination with gefitinib or erlotinib, and is presently in Phase III. Miransertib (ARQ092), developed by ArQule Inc, is well tolerated in humans. In 2019 the company reported the results of Phase I/II clinical trials which showed that the agent is highly active in a subset of endometrial tumors with PI3 K pathway gene mutations, and in proteus syndrome and PIK3CA-related overgrowth spectrum (PROS). Bayer has also developed an allosteric inhibitor, BAY1125976, which is selective for Akt1 and Akt2. The results of a Phase I study were reported in 2019 involving patients with advanced hormone receptor-positive metastatic breast cancer including some harboring the AKT1E17K mutation. Overall, it was well tolerated and inhibited AKT1/2 signaling but did not lead to any tumor responses.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
MK-2206 is the first small molecule allosteric AKT inhibitor to enter clinical trials. MK-2206 inhibits AKT autophosphorylation at Thr 308 and Ser 473, which results in anticancer action257. In the phase II study, MK-2206 had little efficacy in advanced breast cancer patients with genetic alterations or deletions258. The ORR and 6-month PFS were 5.6% for the PIK3CA/AKT1 mutation group, while the ORR was 0% and the 6-month PFS was 11% for the PTEN deletion/mutation group. Toxicity and tumour-related features reduced dose delivery, leading to insufficient tumour target inhibition and ultimately limited anticancer efficacy258. Likewise, MK-2206 monotherapy showed modest activity in renal cell carcinoma and in lymphoma259,260. When MK-2206 was combined with bendamustine and rituximab to treat patients with CLL, the ORR was 92% and the median PFS was 16 months, making it a promising novel therapeutic combination for CLL261. In patients with HER2 amplified solid tumours, MK-2206 was coupled with paclitaxel and trastuzumab, and 10 patients (63%) responded with a median response duration of 6 months262. Although some activity signals were observed in the combination therapy of MK-2206, no new research has been conducted on MK-2206 due to efficacy and tolerance issues.
AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis
Published in Hematology, 2023
Yunjian Li, Liang Du, Kaiqin Ye, Xiao Sun, Lei Hu, Shan Gao, Haiming Dai
PI3K/AKT signaling plays important role in regulating cellular functions. Moreover, activation of PI3K/AKT/mTOR signaling contributes to the pathogenesis of many cancer types. For example, PI3Ks have been reported to be involved in cell growth, proliferation, differentiation and intracellular trafficking, which in turn contribute to cancer development [58]. AKT is functionally activated or deactivated through phosphorylation or dephosphorylation, resulting in different consequences in controlling cell metabolism, growth, proliferation, and survival [59]. The activated AKTs affect cellular proliferation or survival through multiple downstream signaling pathways, such as activating the pathway for the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), or suppression of the p53 pathway [60]. Gsk690690 and MK-2206 are AKT inhibitors that effectively inhibit AKT1, AKT2, and AKT3. In particular, MK-2206 is an allosteric inhibitor of AKT with activity against all three AKT isoforms but has more inhibition against AKT1 and AKT2 [61]. MK-2206 has been under clinical trials for endometrial cancer [62], uterine serous carcinoma [63], and breast cancer [64].
The seamless integration of dietary plant-derived natural flavonoids and gut microbiota may ameliorate non-alcoholic fatty liver disease: a network pharmacology analysis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2023
Ki-Kwang Oh, Haripriya Gupta, Raja Ganesan, Satya Priya Sharma, Sung-Min Won, Jin-Ju Jeong, Su-Been Lee, Min-Gi Cha, Goo-Hyun Kwon, Min-Kyo Jeong, Byeong-Hyun Min, Ji-Ye Hyun, Jung-A Eom, Hee-Jin Park, Sang-Jun Yoon, Mi-Ran Choi, Dong Joon Kim, Ki-Tae Suk
Both luteolin and myricetin are secondary metabolites in natural resources or postbiotics in specific GM. The luteolin improves sensitivity level of insulin as an antidiabetic agent, including antioxidant and anti-inflammatory properties [50]. Likewise, myricetin has not only potent stimulatory effect of insulin, but accelerates lipogenesis in rat adipocytes [51]. The MK-2206 as an AKT inhibitor reached at a phase II clinical trial suppressed the progression of NAFLD [52]. Uncommonly, there was no relationship between CFTR and hepatic steatosis in the development of NAFLD [53]. Wortmannin as PIK3R1 (PI3K) inhibitor diminished the expression level of interleukin 1β (IL-1β) and interleukin 18 (IL-18), which leads to protecting mice from NAFLD [54]. The results suggested that targets (AKT1, PIK3R1) and effectors (luteolin, myricetin) might be critical elements to alleviate NAFLD on a pharmacological viewpoint. Thus, our innovative methodology gives significant clues to clarify the nuanced relationships between GM and DPDNFs.