cml

Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), is formed through the oxidative modification of glycated proteins under conditions of oxidative stress.1,2,3 Its levels escalate with age, diabetes, cancer, vascular diseases, and various pathologies associated with oxidative stress.1,4,5 CML interacts with the membrane-bound receptor for AGEs (RAGE), initiating signaling via MAPKs and NF-κB pathways. Conversely, a truncated version of RAGE generates a soluble protein that sequesters CML, thereby diminishing this signaling.6,7

AN-019 (NRC-019) is a Bcr-Abl kinase inhibitor with antitumor activity for the study of chronic myelogenous leukemia (CML) and breast cancer.

SKLB 1028 (Ruserontinib) is a new type of oral multikinase inhibitor of EGFR, FLT3, and Abl. SKLB 1028 shows excellent activity in FLT3-driven AML models and considerable potency in CML models containing Abl mutants.

BMS-214662 is a potent and selective farnesyl transferase inhibitor that induces mitochondrial apoptosis in primitive CD34+ chronic myeloid leukemia (CML) stem cells/progenitors, and has the ability to selectively target CML stem cells/progenitors with antitumor activity.

CMLD012072 is a potent eukaryotic initiation factor 4A (eIF4A) inhibitor with potent anti-neoplastic activity. It can induce RNA clamping of eIF4A1 and eIF4A2.

CMLD012073 is a potent eukaryotic initiation factor 4A (eIF4A) inhibitor. It inhibits NIH/3T3 cells (IC50: 10 nM). CMLD012073 inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase (eIF4A).

CMLD-2 is an inhibitor of HuR-ARE interaction (Ki: 350 nM) that competitively binds HuR protein and disrupts its interaction with adenine element-rich (ARE) mRNA targets.CMLD-2 induces apoptosis and exhibits antitumor effects through MAD2 downregulation. CMLD-2 (1-75 μM ; 24-72 h) had an inhibitory effect on the viability of thyroid cancer cells.CMLD-2 (20-30 μM ; 24-48 h) activated caspases and induced apoptosis in H1299 and A549 cells.CMLD-2 (30 μM ; 24-48 h) induced G1 cell cycle arrest in H1299 and A549 cells and mitochondrial perturbation. CMLD-2 (30 μM ; 24-48 h) reduced the expression of HuR and HuR-regulated mRNAs and proteins in H1299 cells.CMLD-2 (35 μM ; 72 h) decreased the directional migration ability of SW1736, 8505C, BCPAP and K1 cells.CMLD-2 induced the migration of SW1736, 8505C, BCPAP and K1 cells with a strong decrease in MAD2 mRNA levels.

CMLD010509 (SDS-1-021) is a highly selective inhibitor of the oncogenic translation program supporting multiple myeloma (MM)-including key oncoproteins such as MDM2, CCND1, MYC, MAF, and MCL-1.

CMLD012612 is a potent eukaryotic initiation factor 4A (eIF4A) inhibitor. It inhibits cell translation and is cytotoxic to NIH/3T3 cells (IC50: 2 nM).

Dasatinib monohydrate (BMS-354825 Monohydrate) is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib monohydrate binds to and inhibits the growth-promoting activities of these kinases. Apparently, because of its less stringent binding affinity for the BCR-ABL kinase, Dasatinib monohydrate has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations.

Icaritin (Anhydroicaritin) has hormone regulation activity and cardiovascular function improvement activity. Icaritin has anticancer activity, can induce S phase arrest and apoptosis, inhibit ENKL cell proliferation. Icaritin has anti-multiple myeloma activity, mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling. Icaritin at low concentration (4 or 8 μMol/L) can promote rat chondrocyte proliferation and inhibit cell apoptosis, while the effect of Icaritin on rat chondrocyte at high concentration was reversed.

1. Oroxylin A (Baicalein 6-methyl ether) has various anti-tumor effects including apoptosis, cell cycle arrest, drug-resistant reversion. 2. Oroxylin A possesses abilities of inhibiting the ATRA-induced IL-6 production via modulation of LAP/LIP/CHOP in leukemia cell lines, which could providing a therapeutic strategy for RAS. 3. Oroxylin A inhibits UCP2s triggers the MPTP opening, and promotes the apoptosis in CaCo-2 cells; uncoupling protein 2 plays a key role in mitochondrial apoptotic pathway. 4. Oroxylin A inhibits N1ICD translocating to the nucleus and binding to epithelial-mesenchymal transition-related transcription factor Snail, thus suppressing the invasion and migration of MCF-7 cells. 5. Oroxylin A improves the sensitivity of K562/ADM cells by increasing apoptosis in leukemic cells and decreasing the expression of CXCR4 and PI3K/Akt/NF-κB pathway, and probably served as a most promising agent for CML treatment.

Dasatinib (BMS-354825) is a tyrosine kinase inhibitor that inhibits Src and Bcr-Abl (Ki=16/30 pM) and is orally active and ATP-competitive. Dasatinib has antitumor activity and is used in the treatment of leukemia and lymphoma.

DB0614 (Example 21) is a bifunctional compound designed for the targeted degradation of kinases, effectively breaking down a wide array of kinases including AAK1, AURKA, BMP2K, CAMKK1, CDK16, CML, CDK6, EIF2AK2, FER, GAK, LCK, LIMK2, MAP3KH, MAPK8, MAPK9, NEK9, PLK4, PTK2B, SIK2, STK17A, STK17B, ULK1, ULK3, and WEE1. This compound has potential applications in the research of diseases or disorders caused by aberrant kinase activity [1].

AKI603 is a novel small molecule inhibitor of Aurora kinase A (AurA)(IC50 = 12.3 nM). AKI603 is developed to overcome resistance mediated by BCR-ABL-T315I mutation. AKI603 exhibits strong anti-proliferative activity in leukemic cells[1][2].

SIAIS100 TFA is a potent BCR-ABL PROTAC degrader, exhibiting a DC50 of 2.7 nM. It is utilized in the research of chronic myeloid leukemia (CML) [1].

IST5-002 is a potent inhibitor of Stat5a/b and selectively inhibits the transcriptional activity of Stat5a/b with IC50 values of 1.5 μM and 3.5 μM for Stat5a and Stat5b, respectively. IST5-002 can be used to study prostate cancer and chronic granulocytic leukaemia (CML).

CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor with an IC50 of 21.3 nM against wild-type Bcr-Abl kinase and has anti-chronic myeloid leukemia (CML) activity.

BVB-808 is a selective Jak2 type 1 inhibitor. Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML).

SGX393 is an inhibitor of the CML mutant Bcr-AblT315I, thereby preempting in vitro resistance when combined with nilotinib or dasatinib.

SIAIS100, a potent BCR-ABL PROTAC degrader, demonstrates a DC50 value of 2.7 nM, highlighting its efficacy. It is primarily utilized in the investigation of chronic myeloid leukemia (CML) [1].

LGB-321 is a potent and selective ATP-competitive small molecule inhibitor of PIM kinases (Pan-PIM kinase inhibitor). LGB321 is unique relative to previously described PIM inhibitors, in that it is active in PIM2 dependent cell lines. , a kinase that has proven difficult to inhibit in the cellular context. Consistent with its activity on all three PIM kinases, LGB321 inhibits proliferation of a number of cell lines derived from diverse hematological malignancies, including MM, AML, CML and B-Cell NHL. In vivo, LGB-321 is orally available, demonstrates efficacy in tumor xenografts and is well-tolerated within the therapeutic exposure range in mice. (source: Clin Cancer Res. 2014 Apr 1;20(7):1834-45 )

iHCK-37 (ASN05260065) is a high-potency, selective inhibitor of Hck with a Ki value of 0.22 μM. It effectively inhibits HIV-1 viral replication, exhibiting an EC50 value of 12.9 μM. Primarily employed in chronic myeloid leukemia (CML) research, iHCK-37 demonstrates promising potential for studying and understanding this disease.

Imatinib is a multi-target inhibitor of v-Abl, c-Kit, and PDGFR (IC50: 0.6 μM, 0.1 μM, and 0.1 μM, respectively). Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs), and a number of other malignancies.

Radotinib (IY-5511), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of Y, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other tyrosine kinase Bcr-Abl inhibitors

GNF-7 is Bcr-Abl WT and Bcr-Abl T315I inhibitor with IC50 of 133 nM and 61 nM, respectively.

GNF-5 is a specific non-ATP competitive inhibitor of Bcr-Abl (IC50: 0.22±0.1 uM, Wild-type Abl). It is an analog of GNF-2 with improved pharmacokinetic properties.

Epimedokoreanin B (EKB), an isoprenylated flavonoid isolated from Korean Epimedium, exhibited anticancer activity in human non-small cell lung cancer (NSCLC) A549 and NCI-H292 cells.Epimedokoreanin B also possesses anti-inflammatory and antibacterial activities, and may have scavenging activity against DPPH radicals, inhibiting the proliferation of MCF-7 and HepG2 in a dose-dependent manner. Epimedokoreanin B also exhibits anti-inflammatory and antibacterial activity, with DPPH radical scavenging activity, and inhibits the proliferation of MCF-7 and HepG2 in a dose-dependent manner.Epimedokoreanin B significantly inhibits the formation of N (α)-(carboxymethyl)lysine (CML) and N (Ï)-(carboxymethyl)arginine (CMA), and prevents clinical complications of diabetes mellitus through the inhibition of advanced glycation end-products (AGEs).

CML-IN-1, also known as compound 7 and compound 4, is a potent anticancer agent that demonstrates a strong induced-apoptosis effect in the human chronic myeloid leukemia (CML) cell line K562. It diminishes protein phosphorylation within the PI3K/Akt signaling pathway to exert its effects and suppresses cell proliferation through the inhibition of the MEK/ERK signaling pathway in colorectal cancer [1] [2].

BCR-ABL-IN-7 is a WT and T315I mutant ABL kinase inhibitor.BCR-ABL-IN-7 potently inhibits WT and T315I mutant ABL kinase activity.BCR-ABL-IN-7 can be used in chronic myelogenous leukemia (CML) research.

1. trans-Cinnamaldehyde (Phenylacrolein) exhibits excellent anti-inflammatory activities and antidepressant-like effects in stressed mid-aged rats as a COX-2 inhibitor. 2. Cinnamic aldehyde induces apoptosis of CML cells in vitro, down-regulation of the expression and function of BCR-ABL may be one of its most important anti-leukemia mechanisms. 3. Cinnamic aldehyde and cinnamic acid are cardioprotective in a rat model of ischemic myocardial injury, the mechanism is related to anti-oxidative and anti-inflammatory properties.

16-Hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. 16-Hydroxycleroda-3,13-dien-15,16-olide regulates the expre

CHMFL-ABL-053 (Compound 18a) is a potent, selective, and orally available BCR-ABL, SRC and p38 kinase inhibitor with IC 50 values of 70, 90 and 62 nM against ABL1, SRC and p38, respectively. CHMFL-ABL-053 is a potentially useful drug candidate for Chronic Myeloid Leukemia(CML)[1].

AP23464 is a potent adenosine 5'-triphosphate (ATP)-based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl-transduced Ba/F3 cells (IC(50) = 14 nM. AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl-expressing cells. Biochemical assays with purified glutathione S transferase (GST)-Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warr......

Pivanex (Pivalyloxymethyl butyrate) is an orally active HDAC inhibitor and an antimetastatic and antiangiogenic agent. Pivanex downregulates the Bcr-Abl protein and enhances apoptosis.

Adaphostin (NSC-680410) is a p210Bcr Abl tyrosine kinase inhibitor with IC50 of 14 μM.

Vodobatinib (K-0706) is a novel 3rd generation (3G) TKI effective against wild-type and mutated BCR-ABL1 with limited off-target activity.