Cell Cycle includes many processes necessary for successful self-replication, and consists of DNA synthesis (S) and mitosis (M) phases separated by gap phases in the order G1–S–G2–M. S phase and M phase are usually separated by gap phases called G1 and G2, when cell-cycle progression can be regulated by various intracellular and extracellular signals. In order to move from one phase of its life cycle to the next, a cell must pass through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist. Progression through G1 phase is controlled by pRB proteins, and phosphorylation of pRB proteins by CDKs releases E2F factors, promoting the transition to S phase. The G2/M transition that commits cells to division is a default consequence of initiating the cell cycle at the G1/S transition, many proteins, such Wee1, PLK1 and cdc25, is involved the regulation of this process. The best-understood checkpoints are those activated by DNA damage and problems with DNA replication.

DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Genome instability arises if cells initiate mitosis when chromosomes are only partially replicated or are damaged by a double-strand DNA break (DSB). To prevent cells with damaged DNA from entering mitosis, ATR inhibits cyclin B/Cdk1 activation by stimulating the Cdk1 inhibitory kinase Wee1 and inhibiting Cdc25C via Chk1, besides, ATM and ATR also initiate DNA repair by phosphorylating several other substrates.

In cancer cells, the cell cycle regulators as well as other elements of the DDR pathway have been found to protect tumor cells from different stresses and to promote tumor progression. Thus, cell cycle proteins that directly regulate cell cycle progression (such as CDKs), as well as checkpoint kinases, Aurora kinases and PLKs, are promising targets in cancer therapy.

References:
[1] Rhind N, et al. Cold Spring Harb Perspect Biol. 2012 Oct; 4(10): a005942.
[2] Duronio RJ, et al. Cold Spring Harb Perspect Biol. 2013 Mar; 5(3): a008904.
[3] Liu W, et al. Mol Cancer. 2017 Mar 14;16(1):60.
[4] Ghelli Luserna di Rora' A, et al. J Hematol Oncol. 2017 Mar 29;10(1):77.


Anti-infection >
Arenavirus Bacterial CMV Enterovirus Filovirus Fungal HBV HCV HIV HSV Influenza Virus Parasite Reverse Transcriptase RSV SARS-CoV
Antibody-drug Conjugate >
ADC Cytotoxin ADC Linker Drug-Linker Conjugates for ADC PROTAC-linker Conjugate for PAC
Apoptosis >
Apoptosis Bcl-2 Family c-Myc Caspase DAPK Ferroptosis IAP MDM-2/p53 PKD RIP kinase Survivin Thymidylate Synthase TNF Receptor
Autophagy >
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Antifolate APC ATM/ATR Aurora Kinase Casein Kinase CDK Checkpoint Kinase (Chk) CRISPR/Cas9 Deubiquitinase DNA Alkylator/Crosslinker DNA-PK DNA/RNA Synthesis Eukaryotic Initiation Factor (eIF) G-quadruplex Haspin Kinase HDAC HSP IRE1 Kinesin LIM Kinase (LIMK) Microtubule/Tubulin Mps1 Nucleoside Antimetabolite/Analog p97 PAK PARP PERK Polo-like Kinase (PLK) PPAR RAD51 ROCK Sirtuin SRPK Telomerase TOPK Topoisomerase Wee1
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JAK/STAT Signaling >
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ERK JNK KLF MAP3K MAP4K MAPKAPK2 (MK2) MEK Mixed Lineage Kinase MNK p38 MAPK Raf Ribosomal S6 Kinase (RSK)
Membrane Transporter/Ion Channel >
ATP Synthase BCRP Calcium Channel CFTR Chloride Channel CRAC Channel CRM1 EAAT2 GABA Receptor GlyT HCN Channel iGluR Monoamine Transporter Monocarboxylate Transporter Na+/Ca2+ Exchanger Na+/HCO3- Cotransporter Na+/K+ ATPase nAChR NKCC P-glycoprotein P2X Receptor Potassium Channel Proton Pump SGLT Sodium Channel TRP Channel URAT1
Metabolic Enzyme/Protease >
15-PGDH 5 alpha Reductase 5-Lipoxygenase Acetyl-CoA Carboxylase Acyltransferase Adenosine Deaminase Adenosine Kinase Aldehyde Dehydrogenase (ALDH) Aldose Reductase Aminopeptidase Angiotensin-converting Enzyme (ACE) ATGL ATP Citrate Lyase Carbonic Anhydrase Carboxypeptidase Cathepsin CETP COMT Cytochrome P450 Dipeptidyl Peptidase Dopamine β-hydroxylase E1/E2/E3 Enzyme Elastase Enolase FAAH FABP Factor Xa Farnesyl Transferase Fatty Acid Synthase (FAS) FXR Glucokinase GSNOR Gutathione S-transferase HCV Protease Hexokinase HIF/HIF Prolyl-Hydroxylase HIV Integrase HIV Protease HMG-CoA Reductase (HMGCR) HSP Indoleamine 2,3-Dioxygenase (IDO) Isocitrate Dehydrogenase (IDH) Lactate Dehydrogenase LXR MAGL Mineralocorticoid Receptor Mitochondrial Metabolism MMP Nampt NEDD8-activating Enzyme Neprilysin PAI-1 PDHK PGC-1α Phosphatase Phosphodiesterase (PDE) Phospholipase Procollagen C Proteinase Proteasome Pyruvate Kinase RAR/RXR Renin ROR Ser/Thr Protease SGK Stearoyl-CoA Desaturase (SCD) Thrombin Tryptophan Hydroxylase Tyrosinase Xanthine Oxidase
Neuronal Signaling >
5-HT Receptor AChE Adenosine Kinase Amyloid-β Beta-secretase CaMK CGRP Receptor COMT Dopamine Receptor Dopamine Transporter FAAH GABA Receptor GlyT iGluR Imidazoline Receptor mAChR Melatonin Receptor Monoamine Oxidase nAChR Neurokinin Receptor Opioid Receptor Serotonin Transporter γ-secretase
NF-κB >
NF-κB IKK Keap1-Nrf2 MALT1
PI3K/Akt/mTOR >
Akt AMPK ATM/ATR DNA-PK GSK-3 MELK mTOR PDK-1 PI3K PI4K PIKfyve PTEN
PROTAC >
PROTAC E3 Ligase Ligand-Linker Conjugate Ligand for E3 Ligase PROTAC Linker PROTAC-linker Conjugate for PAC
Protein Tyrosine Kinase/RTK >
Ack1 ALK Bcr-Abl BMX Kinase Btk c-Fms c-Kit c-Met/HGFR Discoidin Domain Receptor DYRK EGFR Ephrin Receptor FAK FGFR FLT3 IGF-1R Insulin Receptor IRAK Itk PDGFR PKA Pyk2 ROS Src Syk TAM Receptor Trk Receptor VEGFR
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Vitamin D Related >
VD/VDR
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Androgen Receptor Aromatase Estrogen Receptor/ERR Progesterone Receptor Thyroid Hormone Receptor Others

Riviciclib

Riviciclib (P276-00 free base) is a potent CDK9-cyclinT1, CDK4-cyclin D1, CDK1-cyclinB, CDK2-cyclin A, CDK2-cyclin E, CDK6-cyclin D3, and CDK9-cyclin H inhibitor with IC50 values of 20 nM, 63 nM, 79 nM, 224 nM, 2500 nM, 396 nM, 2900 nM, respectively[1].Riviciclib shows antitumor activity on cisplatin-resistant cells[3].

  • CAS Number: 920113-02-6
  • MF: C21H20ClNO5
  • MW: 401.84
  • Catalog: CDK
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

6-Methyl-9-(2-β-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine

6-Methyl-9-(2-β-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 2095417-61-9
  • MF: C33H28N4O7
  • MW: 592.60
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

N2-iBu-5’-O-DMTr-2’-O-hexadecanyl guanosine 3’-CED phosphoramidite

N2-iBu-5’-O-DMTr-2’-O-hexadecanyl guanosine 3’-CED phosphoramidite is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 2382942-32-5
  • MF: C60H86N7O9P
  • MW: 1080.34
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

PPARγ agonist 4

PPARγ agonist 4 (Compound 18b) is a potent and selective agonist of PPARγ. PPARγ agonist 4 is not cytotoxic neither on non-resistant nor on resistant cells. PPARγ agonist 4 exerts antitumor potency only in combination with Imatinib[1].

  • CAS Number: 2380227-06-3
  • MF: C24H22FN3O
  • MW: 387.45
  • Catalog: PPAR
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

epicylindrospermopsin

Cylindrospermopsin is a cyanotoxin produced by a variety of freshwater cyanobacteria. It is a polycyclic uracil derivative containing guanidine and sulfate groups, which can inhibit protein synthesis and covalently modify DNA or RNA[1].

  • CAS Number: 143545-90-8
  • MF: C15H21N5O7S
  • MW: 415.422
  • Catalog: DNA/RNA Synthesis
  • Density: 2.0±0.1 g/cm3
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

5-(2-bromovinyl)-2'-deoxyuridine-5'-triphosphate

BVDU 5′-Triphosphate is an antivirus agent with 5′-Triphosphate label, targeting viral DNA polymerase. BVDU 5′-Triphosphate shows excellent selectivity against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1), due to a specific phosphorylation by the virus-encoded thymidine kinase.

  • CAS Number: 77222-61-8
  • MF: C11H16BrN2O14P3
  • MW: 573.08
  • Catalog: HSV
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

CEM114

CEM114 is an effective chemical epigenetic modifier (CEM) that recruits endogenous chromatin machinery through CRISPR-Cas9 systems[1].

  • CAS Number: 2279062-54-1
  • MF: C84H122FN9O19S
  • MW: 1612.98
  • Catalog: CRISPR/Cas9
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

5-O-(tert-Butyldiphenylsilyl)-2,3-isopropylidene-D-ribonolactone

5-O-(tert-Butyldiphenylsilyl)-2,3-isopropylidene-D-ribonolactone is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 130222-84-3
  • MF: C24H30O5Si
  • MW: 426.58
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

BI-1347

BI-1347 is a potent CDK8 inhibitor extracted from patent WO2017202719A1, product I-003, has an IC50 of 1.1 nM[1].

  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

Vindoline

Vindoline, a vinca alkaloid extracted from the leaves of Catharanthus roseus, weakly inhibits tubulin self-assembly[1].

  • CAS Number: 2182-14-1
  • MF: C25H32N2O6
  • MW: 456.531
  • Catalog: Microtubule/Tubulin
  • Density: 1.3±0.1 g/cm3
  • Boiling Point: 569.8±50.0 °C at 760 mmHg
  • Melting Point: 163-165ºC
  • Flash Point: 298.4±30.1 °C

Anticancer agent 60

Anticancer agent 60 (compound 3h) has antiproliferative activity against human HepG2 cells (IC50 = 4.13 μM) and presents antitumor efficacy in a human HepG2 xenograft mouse model[1].

  • CAS Number: 2162169-14-2
  • MF: C27H33N5O4S
  • MW: 523.65
  • Catalog: Microtubule/Tubulin
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

Mefuparib hydrochloride(CVL218)

Mefuparib hydrochloride is a potent, highly selective, competitive PARP1/2 inhibitor with IC50 of 3.2/1.9 nM, respectively; displays >406-fold over other major nuclear PARPs including PARP3, TNKS1, TNKS2 and PARP6; reduces poly(ADP-ribose) formation, enhances γH2AX levels, induces G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells; shows potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide.

  • CAS Number: 1449746-00-2
  • MF: C17H16ClFN2O2
  • MW: 334.775
  • Catalog: Apoptosis
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

CK2-IN-6

CK2-IN-6 is a potent protein kinase CK2 inhibitor that can be used in the study of cancer as well as other kinase-related conditions, including inflammation, pain and certain immune diseases[1].

  • CAS Number: 1309835-18-4
  • MF: C19H16ClN7O2
  • MW: 409.83
  • Catalog: Casein Kinase
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

Tamoxifen-d3

Tamoxifen-d3 is the deuterium labeled Tamoxifen[1]. Tamoxifen (ICI 47699) is an orally active, selective estrogen receptor modulator (SERM) which blocks estrogen action in breast cells and can activate estrogen activity in other cells, such as bone, liver, and uterine cells[2][3][4]. Tamoxifen is a potent Hsp90 activator and enhances the Hsp90 molecular chaperone ATPase activity. Tamoxifen also potent inhibits infectious EBOV Zaire and Marburg (MARV) with IC50 of 0.1 μM and 1.8 μM, respectively[6]. Tamoxifen activates autophagy and induces apoptosis[5]. Tamoxifen also can induce gene knockout of CreER(T2) transgenic mouse[7].

  • CAS Number: 508201-30-7
  • MF: C26H26D3NO
  • MW: 374.53
  • Catalog: Apoptosis
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

N2,2'-O-Dimethylguanosine

N2,2'-O-Dimethylguanosine is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 135023-21-1
  • MF: C12H17N5O5
  • MW: 311.29
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

tubulin polymerization inhibitor

Tubulin polymerization-IN-24 (compound HMBA) is a potent tubulin polymerization inhibitor. Tubulin polymerization-IN-24 inhibits MCF-7 cells proliferation. Tubulin polymerization-IN-24 induces apoptosis and cell cycle arrest at G2/M phase. Tubulin polymerization-IN-24 increase the GTP hydrolysis rate and inhibits microtubule assembly[1].

  • CAS Number: 564468-51-5
  • MF: C22H16O3
  • MW: 328.361
  • Catalog: Apoptosis
  • Density: 1.3±0.1 g/cm3
  • Boiling Point: 524.7±50.0 °C at 760 mmHg
  • Melting Point: N/A
  • Flash Point: 188.8±23.6 °C

Clk1/2-in-3

LK1/2-IN-3 (compound 3) is a potent and selective CLK1 and CLK2 inhibitor with IC50 values of 1.1, 2.1, 130, 260, 260 nM for CLK1, CLK2, SRPK1, SRPK2, SRPK3, respectively. CLK1/2-IN-3 shows anti-proliferative activity. CLK1/2-IN-3 reduces the levels of endogenous phosphorylated SR proteins and increases the expression of S6K mRNAs[1].

  • CAS Number: 1005784-60-0
  • MF: C21H21N5O2
  • MW: 375.42
  • Catalog: CDK
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A
  • CAS Number: 184302-49-6
  • MF: C9H12FN3O3S
  • MW: 261.273
  • Catalog: DNA/RNA Synthesis
  • Density: 1.8±0.1 g/cm3
  • Boiling Point: 516.5±60.0 °C at 760 mmHg
  • Melting Point: N/A
  • Flash Point: 266.2±32.9 °C

Cdk4/6 Inhibitor IV

Cdk4/6 Inhibitor IV is a cell-permeable triaminopyrimidine compound acting as a reversible and ATP-competitive inhibitor of Cdk4/6 (IC50 = 1.5 ��M and 5.6 ��M for Cdk4/D1 and Cdk6/D1, respectively)

  • CAS Number: 359886-84-3
  • MF: C27H32N6O
  • MW: 456.583
  • Catalog: CDK
  • Density: 1.3±0.1 g/cm3
  • Boiling Point: 755.4±70.0 °C at 760 mmHg
  • Melting Point: N/A
  • Flash Point: 410.6±35.7 °C

CCG-232964

CCG-232964 is an orally active inhibitor of Rho/MRTF/SRF. CCG-232964 inhibits LPA-induced CTGF gene expression[1].

  • CAS Number: 2349373-70-0
  • MF: C15H15ClN2O3S
  • MW: 338.81
  • Catalog: ROCK
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

N1-Ethylpseudouridine

N1-Ethylpseudouridine is a purine nucleoside analogue. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 1613529-72-8
  • MF: C11H16N2O6
  • MW: 272.25
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

(2S,3R)-Voruciclib

(2S,3R)-Voruciclib is the (2S,3R)-enantiomer of Voruciclib. (2S,3R)-Voruciclib is an orally active CDK inhibitor[1].

  • CAS Number: 1253731-24-6
  • MF: C22H19ClF3NO5
  • MW: 469.84
  • Catalog: CDK
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

HDAC4-IN-1

HDAC4-IN-1 (compound 1a) is a class IIa HDACI inhibitor (IC50=0.077 μM). HDAC4-IN-1 can enhance Caspase-induced Apoptosis. HDAC4-IN-1 has anticancer activity. HDAC4-IN-1 can be used in the research of drug combination against cancer[1].

  • CAS Number: 1418293-39-6
  • MF: C16H19F3N4O2
  • MW: 356.34
  • Catalog: Apoptosis
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

Acelarin

Acelarin (NUC-1031) is a ProTide transformation and enhancement of the widely-used nucleoside analogue, gemcitabine.

  • CAS Number: 840506-29-8
  • MF: C25H27F2N4O8P
  • MW: 580.47400
  • Catalog: DNA/RNA Synthesis
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

Nalidixic acid sodium salt

Nalidixic acid sodium salt, a quinolone antibiotic, is effective against both gram-positive and gram-negative bacteria. Nalidixic acid acts in a bacteriostatic manner in lower concentrations and is bactericidal in higher concentrations. Nalidixic acid inhibits a subunit of DNA gyrase and topoisomerase IV and reversibly blocks DNA replication in susceptible bacteria[1][2].

  • CAS Number: 3374-05-8
  • MF: C12H11N2NaO3
  • MW: 254.21700
  • Catalog: Bacterial
  • Density: 1.331g/cm3
  • Boiling Point: 413.1ºC at 760mmHg
  • Melting Point: 229-230ºC
  • Flash Point: 203.6ºC

N2-iBu-5’-O-DMTr-2’-O-hexadecanyl guanosine

N2-iBu-5’-O-DMTr-2’-O-hexadecanyl guanosine is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 2382942-31-4
  • MF: C51H69N5O8
  • MW: 880.12
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

BSJ-04-132

BSJ-04-132 is a potent and selective Ribociclib-based CDK4 degrader (PROTAC), with IC50s of 50.6 nM and 30 nM for CDK4/D1 and CDK6/D1, respectively. BSJ-04-132 does not induce CDK6 and IKZF1/3 degradation. BSJ-04-132 has anti-cancer activity[1].

  • CAS Number: 2349356-39-2
  • MF: C42H49N11O7
  • MW: 819.91
  • Catalog: CDK
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

6-Amino-9-[2-deoxy-β-D-ribofuranosyl]-9H-purine

6-Amino-9-[2-deoxy-β-D-ribofuranosyl]-9H-purine is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 148171-35-1
  • MF: C10H13N5O3
  • MW: 251.24
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

DNA Gyrase-IN-2

DNA Gyrase-IN-2 (Compound 22a) is a bacterial DNA gyrase B inhibitor with IC50s of 3.29-10.49 and 4.41-5.61 µM for E. coli DNA gyrase and M. tuberculosis DNA gyrase. Anti-tubercular and antibacterial activity[1].

  • CAS Number: 2522666-80-2
  • MF: C24H24N8OS2
  • MW: 504.63
  • Catalog: Bacterial
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A

5’-Azido-5’-deoxy-2’-O-(2-methoxyethyl)uridine

5’-Azido-5’-deoxy-2’-O-(2-methoxyethyl)uridine is a purine nucleoside analog. Purine nucleoside analogs have broad antitumor activity targeting indolent lymphoid malignancies. Anticancer mechanisms in this process rely on inhibition of DNA synthesis, induction of apoptosis, etc[1].

  • CAS Number: 2095417-60-8
  • MF: C12H17N5O6
  • MW: 327.29
  • Catalog: Nucleoside Antimetabolite/Analog
  • Density: N/A
  • Boiling Point: N/A
  • Melting Point: N/A
  • Flash Point: N/A