dna damage response

AGI-24512 is a potent inhibitor of methionine adenylyltransferase 2α (MAT2A) (IC50: 8 nM).AGI-24512 shows antiproliferative activity in MTAP-deficient cancer cells.AGI-24512 inhibits MAT2A, which causes DNA damage in MTAP, and is often used in conjunction with anticancer compounds in cancer research.

Elimusertib (BAY-1895344) is a potent, highly selective, and orally available ATR inhibitor with an IC50 of 7 nM, demonstrating significant anti-tumor efficacy as a monotherapy and strong combination potential with targeted alpha therapy Radium-223 dichloride.

SSK1 is a compound that selectively kills senescent cells and is a precursor for β-galactosidase, which can reduce the inflammatory response of the body. SSK1 can activate the phosphorylation of p38 MAPK and MKK3/MKK6 in senescent cells, and promote mitochondrial DNA damage in senescent cells.

L-Glutamic acid monosodium salt monohydrate (MSG monohydrate) is an important food additive with gastrointestinal protective effects. It plays a critical role in nutrient metabolism, energy demand, immune response, oxidative stress, signal transduction, and synaptic transmission. L-Glutamic acid monosodium salt monohydrate can induce oxidative stress, DNA damage, and apoptosis in mouse liver and brain tissues. It can protect against gastrointestinal damage caused by NSAIDs and Helicobacter pylori through multiple mechanisms.

BLM-IN-1 is a potent inhibitor of Bloom syndrome protein (BLM) with a KD of 1.81 μM and IC50 of 0.95 μM. It induces DNA damage response, apoptosis, and proliferation arrest in cancer cells.

BMH-21, a small molecule DNA intercalator, binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription and not affects phosphorylation of H2AX.

KL-50, a selective toxin, effectively targets tumors deficient in the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT), which corrects O6-alkylguanine lesions. This compound induces both DNA damage response pathways and cell cycle arrest in MGMT-deficient cells, regardless of mismatch repair (MMR) status. KL-50 shows promise in the study of brain tumors lacking MGMT.

Adenosine 5′-diphosphoribose (ADP ribose), formed from adenosine monophosphate (AMP) and ribose via phosphoribosyl pyrophosphate, is a multifunctional modifier of proteins and nucleic acids, playing crucial roles in diverse cellular processes.

CDK12/13-IN-3 (Compound 12b) is an orally active CDK inhibitor targeting CDK12 and CDK13, with IC50 values of 107.4 nM and 79.4 nM, respectively. This compound inhibits the phosphorylation of Ser2 on the CTD of RNA polymerase II, induces DNA damage, and downregulates the gene expression involved in the DNA damage response (DDR). CDK12/13-IN-3 exhibits antiproliferative effects against various cancer cells with nanomolar IC50 values. In mouse models, it demonstrates antitumor activity, favorable pharmacokinetic properties, and an oral bioavailability of 53.6%.

CHK1-IN-12 (Compound example 1-5) is a highly selective and orally active checkpoint kinase 1 (CHK1) inhibitor, demonstrating an in vitro enzyme IC50 of ≤10 nM and a cellular IC50 of ≤50 nM. This compound suppresses the phosphorylation activity of CHK1 kinase, disrupts DNA damage response pathways, and induces tumor cell cycle arrest and apoptosis. CHK1-IN-12 shows promise for cancer research applications.

CX5461 is an rRNA synthesis inhibitor with oral activity that inhibits Pol I-driven rRNA transcription. CX5461 activates the DNA damage response and has antitumor activity in tumors such as ovarian cancer.

PDIC-NN dimethanesulfonate (PDIC-NS) is a STING activator with anticancer properties. It increases the levels and stability of endogenous cyclic dinucleotides (CDN). PDIC-NN dimethanesulfonate triggers a burst of reactive oxygen species (ROS) and causes significant mitochondrial damage. It induces apoptosis and inhibits DNA replication. Additionally, it activates the cGAS-STING signaling pathway, enhancing the immunogenicity of tumor cells and triggering a strong innate immune response.

NU 9056 is an effective and selective inhibitor of KAT5 histone acetyltransferase with an IC50 of 2 µM. NU 9056 blocks DNA damage response and inhibits protein acetylation in prostate cancer cell lines.

Ryuvidine is a dual inhibitor of KDM5A and SETD8, an inducer of the DNA damage response with potential anticancer activity, inhibition of H4K20 methylation, and inhibition of CDK4, and can be used to study breast cancer and erythroplasia.

DDRI-18 is a novel small molecule inhibitor that regulates the DNA damage response with sensitizing and anticancer activities, inhibits non-homologous end-joining (NHEJ) DNA repair and enhances the cytotoxicity of anticancer DNA damage compounds.

BMVC4 is a G-quadruplex stabilizer. BMVC4 induces senescence by activation of pathways of response to DNA damage that was independent of its telomerase inhibitory activity.

Bardoxolone (CDDO) is a synthetic oleanane triterpenoid that blocks the cellular synthesis of inducible nitric oxide synthase and inducible COX-2 in INF-γ-activated mouse macrophages with an IC50 value of 0.4 nM. By suppressing reactive oxygen and nitrogen species (ROS/RNS) formation, it promotes the cellular control of ROS/RNS levels that would lead to DNA damage associated with tumorigenesis. In various Y cell lines, Bardoxolone has been shown to specifically inhibit proliferation and induce apoptosis. Mechanism studies revealed that Bardoxolone is a ligand for peroxisome proliferator-activated receptor γ, and also that it induces genes regulated by Nrf2, including heme oxygenase-1 and eotaxin-1, which play a role in antioxidant response element signaling activity.

Phosphoramide mustard cyclohexanamine is the active metabolite of cyclophosphamide, an alkylating agent that cross-links DNA strands, organizes cell division and causes cell death, and has antitumor activity.

Potent Chk2 inhibitor (IC50 = 3 nM). Shows >63-fold selectivity for Chk1 over Chk2 and a panel of 84 other kinases. Inhibits Chk2 activation in response to etoposide-induced DNA damage in HT29 cells. Blocks ionizing radiation-induced apoptosis of mouse thymocytes. Caldwell et al (2011) Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2. J.Med.Chem. 54 580 PMID:21186793

The protein p53, often called the 'guardian of the genome,' is a transcription factor that is activated in response to cellular stress (low oxygen levels, heat shock, DNA damage, etc.) and acts to prevent further proliferation of the stressed cell by promoting cell cycle arrest or apoptosis. Its role as a tumor suppressor is evident by the observation that approximately 50% of human tumors have mutated or non-functional p53. PK7242 is an inducer of reactivation of mutant p53 in cancer cells. In cancer cells carrying the Y220C mutant, PK7242 binds to the p53-Y220C core domain and induces growth inhibition, cell-cycle arrest, and apoptosis.

IMP-1700 is an inhibitor of bacterial DNA repair.1It potentiates the activity of the quinolone antibiotic ciprofloxacin against methicillin-resistantS. aureus(MRSA) with a combination index value of 0.7. IMP-1700 inhibits the ciprofloxacin-induced bacterial SOS response, a process that repairs DNA damage, in a reporter assay in a concentration-dependent manner. It is also active againstE. coli, as well as methicillin-resistant and -sensitive S. aureus, when used alone (EC50s = 0.5, 0.21, and 3.8 μM, respectively). 1.Lim, C.S.Q., Ha, K.P., Clarke, R.S., et al.Identification of a potent small-molecule inhibitor of bacterial DNA repair that potentiates quinolone antibiotic activity in methicillin-resistant Staphylococcus aureusBioorg. Med. Chem.27(20)114962(2019)

Tricarbonyldichlororuthenium(II) dimer (CORM-2) is a CO-releasing molecule with anti-inflammatory, antioxidant, and gastroprotective effects. It also modulates potassium channels independently of CO.

BTX161 is a Thalidomide analogue. BTX161 is a potent CKIα degrader. In human AML cells, BTX161 mediates the CKIα degradation better than Lenalidomide as well as activates DNA damage response (DDR) and p53, and also stabilizes the p53 antagonist MDM2[1].

ATR-IN-11 (Compound Hit01) is a potent inhibitor of ataxia capillaris and Rad3-related (ATR) kinases. As a promising lead compound for developing drugs targeting the ATR kinase, a key regulatory protein in the DNA damage response (DDR) that senses replication stress (RS), ATR-IN-11 has significant potential for cancer research.