Cell Cycle/Checkpoint

Adavosertib (MK-1775) is a small molecule inhibitor of the checkpoint kinase WEE1 (IC50: 5.2 nM). It hinders the G2 DNA damage checkpoint.

SCH900776 (MK-8776) is an agent targeting cell cycle checkpoint kinase 1 (Chk1) with potential radiosensitization and chemosensitization activities.

Rabusertib (IC-83) is an inhibitor of the cell cycle checkpoint kinase 1 (chk1) with potential chemopotentiating activity. Rabusertib has been used in trials studying the treatment of Cancer, Solid Tumors, Advanced Cancer, Pancreatic Neoplasms, and Non-Small Cell Lung Cancer.

GDC0575 monohydrochloride (ARRY575) is a potent and selective inhibitor of cell cycle checkpoint kinase 1 (Chk1) with an IC50 of 1.2 nM. GDC-0575 specifically binds to and inhibits Chk1; this may result in tumor cells bypassing Chk1-dependent cell cycle arrest in the S and G2 M phases, which permits the cells to undergo DNA repair prior to entry into mitosis.

TopoisomeraseI inhibitor 17 (Compound 7h) is an inhibitor of TopoisomeraseI (Top1). It reduces DDX5 and reverses the locking effect of DDX5 on Top1 activity. This compound induces Top1-mediated DNA damage and promotes reactive oxygen species (ROS) production. It triggers apoptosis by decreasing anti-apoptotic proteins XIAP, Bcl-2, and Survivin, while increasing pro-apoptotic proteins Bax and γH2AX. Moreover, TopoisomeraseI inhibitor 17 halts progression at the G2 M checkpoint, leading to cell cycle arrest. It significantly impairs colorectal cancer cell colony formation and migration, and effectively reduces tumor size in human PDX tumor mouse models.

Filanesib (ARRY-520) targets the kinesin spindle protein (KSP) with potential antineoplastic activity. ARRY-520 specifically inhibits KSP (kinesin-5 or Eg5), resulting in activation of the spindle assembly checkpoint, induction of cell cycle arrest during

Prexasertib Mesylate Hydrate (LY2606368 Mesylate Hydrate) is an ATP-competitive, selective, second-generation cell cycle checkpoint kinase 1 (CHK1) inhibitor (IC50<1 nM, Ki: 0.9 nM). It inhibits CHK2 (IC50: 8 nM) and RSK1 (IC50: 9 nM), induces double-stranded DNA breaks and replication mutations, triggers apoptosis, and exhibits potent anti-tumor effects.

AZD4877 is a synthetic kinesin spindle protein (KSP) inhibitor with potential antineoplastic activity. KSP inhibitor AZD4877 selectively inhibits microtubule motor protein KSP (also called kinesin-5 or Eg5), which may result in the inhibition of mitotic spindle assembly; activation of the spindle assembly checkpoint; induction of cell cycle arrest during the mitotic phase; and cell death in tumor cells that are actively dividing. Because KSP is not involved in postmitotic processes, such as neuronal transport, this agent may be less likely to cause the peripheral neuropathy often associated with the tubulin-targeting agents. Eg5 is essential for the formation of bipolar spindles and the proper segregation of sister chromatids during mitosis.

Hymenialdisine Analogue #1 is the indole derivative of Hymenialdisine, a potent inhibitor of a variety of kinases including MEK-1, GSK-3Β, and CKI. It also exhibits inhibition of the G2 cell cycle checkpoint at the micromolar concentrations.

CBP501 is a peptide with G2 checkpoint-abrogating activity. G2 checkpoint inhibitor CBP501 inhibits multiple serine threonine kinases, including MAPKAP-K2, C-Tak1, and CHK1, that phosphorylate serine 216 of the dual-specific phosphatase Cdc25C (cell division checkpoint 25 C); disruption of Cdc25C activity results in the inhibition of Cdc25C dephosphorylation of the mitotic cyclin-dependent kinase complex Cdc2 cyclin B, preventing entry into the mitotic phase of the cell cycle.

DW532 is one of simplified analogues of hematoxylin that has shown broad-spectrum inhibition on tyrosine kinases and in vitro anti-cancer activities. DW532 inhibited EGFR and VEGFR2 in vitro kinase activity (the IC50 values were 4.9 and 5.5 μmol L, respectively), and suppressed their downstream signaling. DW532 dose-dependently inhibited tubulin polymerization via direct binding to tubulin, thus disrupting the mitotic spindle assembly and leading to abnormal cell division. In a panel of human cancer cells, DW532 (1 and 10 μmol L) induced G2 M phase arrest and cell apoptosis, which subsequently resulted in cytotoxicity. Knockdown of BubR1 or Mps1, the two core proteins of the spindle assembly checkpoint dramatically decreased DW532-induced cell cycle arrest in MDA-MB-468 cells. Moreover, treatment with DW532 potently and dose-dependently suppressed angiogenesis in vitro and in vivo. ( Acta Pharmacol Sin. 2014 Jul;35(7):916-28.)

GW814408X, a kinase chemical genome group (KCGS) compound, inhibits the AURKC kinase, which is involved in cell cycle progression, checkpoint regulation, and cell division. It exhibits cell line-dependent toxicity, such as cytotoxic effects on HeLa cells, and acts as a protein kinase inhibitor across ATP-dependent and -independent luciferases, potentially impacting Fluc reporter assays [1].