Isogranulatimide - a CHK1 inhibitor
One of the most frequently mutated genes in human cancer is p53 where approximately 50% of all tumors show mutations in this gene. Clearly p53 is important and one of its major functions is in DNA damage-induced cell cycle checkpoints which are paramount for proper functioning of cellular DNA repair mechanisms. Chemotherapeutic agents such as topotecan hydrochloride (Hycamptin®) and doxorubicin (Doxil®) as well as radiotherapy work by damaging DNA and those cancer cells containing non-functional p53 are unable to arrest at the G1 checkpoint thus allowing mutations in the damaged DNA to be propagated by completing their cell cycle through the G2 checkpoint. This appears to be one of the explanations why cancer cells develop resistance to chemotherapeutic agents. Very recent studies have begun to explore ways of bypassing this desensitization by forcing the cancer cells into mitotic cell death through inhibition of the G2 checkpoint. Therefore, it has been hypothesized that treatment with DNA-damaging chemotherapy or radiotherapy in combination with drugs that inhibit the G2 checkpoint could promote the selective killing of cancer cells bearing p53 mutations thus providing therapeutic benefit.
Alethia is developing a G2 checkpoint inhibitor that has been integrated into our current ovarian cancer program. Isogranulatimide (AB-IsoG) is the first G2 checkpoint inhibitors that was discovered in a rational cell-based assay designed specifically to identify these types of small molecules. Much of the preliminary studies have been conducted including drug optimization, target identification, structure determination of the molecule bound to its target, and synthesis.
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