P53 upstream & synthetic lethal: the target "ATM" track has great potential!

The success of PARP inhibitors has turned "synthetic lethality" from a concept into a reality; the continued hotness of P53 has enabled the surrounding targets to prosper together; at the same time, targets with the above characteristics will naturally not be missed by researchers, and ATM is like this One of the targets
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At present, ATM is still in the early stage of target development, clinical varieties have not yet gathered, and the research and development track has great potential! 01 ATM target features ATM (Ataxia Telangiectasia Mutated), ataxia telangiectasia mutation, is a serine/threonine protein; the protein structure of ATM, the N-terminus is unique to ATM, and the C-terminus is related to PIKK family (such as ATR , DNA-PK) CFAT domain (FATC) shared by other members; in addition, the N-terminus also includes some other specific binding domains, as shown in the figure below
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02 DSB damage repair & ATM signal activation Normally, ATM exists as a multimer inactive form.
After DNA single-stranded damage (DSB), ATM is phosphorylated into an activated monomer form
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The repair protein-related complex once again recruits activated ATM, MDC1 and 53BP1 to DSB; at the same time, ATM phosphorylates BRCA1, MDC1 and 53BP1, thereby initiating the DNA damage repair mechanism
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Once DSB occurs, ATM is first catalytically activated; however, the total level of ATM does not change.
A part of ATM rapidly accumulates to DNA damage sites in the nucleus, and the other part is still located in the nucleoplasm; further studies have found that cells that have not undergone DNA damage In the quiescent phase, ATM exists as a dimer, and once activated, it will decompose into an activated monomer form
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After ATM phosphorylation, it will successively regulate the activities of other kinases, such as cell cycle checkpoint kinase 2 (CHK2); in addition, P53 has been used as a marker for ATM activation, and its mechanism of action has also been extensively studied; for example, DNA-PK, AKT and homeodomain binding protein kinase 2 (HIPK2) are also common substrates of ATM
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Among them, activated P53 eventually up-regulates the expression levels of a series of genes.
These genes include both cell cycle checkpoint-related genes to promote cell survival, and programmed cell death-related genes to promote cell death
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03 ATM and tumors The relationship between ATM and tumors mainly acts on cell cycle arrest and apoptosis.
For tumor cells themselves, in order to maintain survival, always reduce ATM expression levels to avoid the influence of ATM activation
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Numerous studies have also found that breast cancer, oral cancer, melanoma, prostate cancer, and pancreatic cancer have all found abnormal ATM expression, and up-regulation is the main feature
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More preclinical/clinical trial studies have shown that: in terms of chemotherapy resistance, tumor cells can increase the levels of P38 and HMGA to promote ATM gene expression; in terms of radiotherapy resistance, due to the high expression of ATM in tumor cells, radiation resistance The tumor cells are resistant to chemotherapy; in terms of survival, ATM can also activate AKT to promote tumor cell survival
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In addition, because the research positioning of ATM is more inclined to synthetic lethality, there are relatively more clinical applications of combined use with other drugs
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04 ATM clinical drug status Through database query, there are currently 3 ATM inhibitors currently entering the clinical stage, namely AZD-1390, M-4076, and XRD-0394; they are introduced as follows
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? AZD-1390 development company is AstraZeneca, orally administered, as an ATM kinase inhibitor, used to treat tumors, including glioblastoma and metastatic brain cancer
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In June 2017, an open-label, single-center, exploratory phase I study analyzed the brain exposure of AZD-1390 (using intravenous [11C]AZD-1390 microdose) in healthy men (n=8).
Median Tmax is 20 minutes
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In April 2018, a phase I trial for patients with recurrent/primary glioblastoma and brain metastases was launched in the United Kingdom and the United States to evaluate safety, tolerability, and pharmacokinetics
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In September 2020, a study was launched to evaluate the safety of the combination of AZD1390 and olaparib
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? M-4076 development company is Merck KGaA, orally administered, is an ATP-competitive, highly selective small molecule ATM inhibitor that can enhance the effect of DNA double-strand break inducers (such as radiotherapy) for cancer treatment, Advanced solid tumors including squamous cell carcinoma of the head and neck
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In May 2021, a human first, open-label, sequential allocation, two-part phase I trial was launched in the United States and Canada to determine the safety of M-4076 monotherapy in participants with advanced solid tumors (expected n=30) Characteristics of resistance, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and early pharmacodynamics
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Another early preclinical test showed that in the p53 mutant HBCx-9 model, M-4076 (30mg/kg, qd) combined with PARP inhibitors showed significant synergistic anti-tumor activity
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? XRD-0394 development company is X Rad Therapeutics, which is administered orally and is a dual ATM/DNA-PK inhibitor for the treatment of metastatic, locally advanced or recurrent solid tumors
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In August 2021, a human first, multicenter, open-label, non-randomized Phase Ia study was launched in the United States to evaluate the safety and tolerability of a single dose; another trial will also evaluate single-dose XRD- PK curve and PD efficacy of 0394 combined with palliative radiotherapy
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