- A new method for the chemical synthesis of the Wee1 protein kinase inhibitor adavosertib
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The present invention relates to a New Method for the Chemical Synthesis of a Weather1 protein kinase inhibitor adavosertib. The method of the present invention, using an intermediate compound that is commercially readily available, which undergoes a micr
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- Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy
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WEE1 kinase regulates the G2/M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.
- Matheson, Christopher J.,Casalvieri, Kimberly A.,Backos, Donald S.,Reigan, Philip
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p. 1681 - 1694
(2018/08/01)
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- COMPOSITIONS AND METHODS FOR TREATING CANCER
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The instant invention relates to methods for the treatment of WEE1 kinase associated cancer by administering a WEE1 inhibitor, wherein the WEE1 inhibitor is WEE1-1 or a pharmaceutically acceptable salt thereof, or WEE1-2 or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a method for treating a WEE1 kinase associated cancer patient, comprising administering a WEE1 inhibitor, wherein the cancer cells of said patient to be treated are characterized by low expression levels of PKMYT1.
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- COMPOSITIONS AND METHODS FOR TREATING CANCER
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The instant invention relates to methods for the treatment of neuroblastoma by administering a combination of a WEE1 inhibitor and a CHK1 inhibitor, wherein the WEE1 inhibitor is WEE1-1 or a pharmaceutically acceptable salt thereof, or WEE1-2 or a pharmaceutically acceptable salt thereof, and the CHK1 inhibitor is CHK1-1 or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a method for treating a neuroblastoma patient, comprising administering a WEE1 inhibitor and a CHK1 inhibitor, wherein the cancer cells of said patient to be treated are characterized by amplified expression levels of MYCN.
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Page/Page column 32
(2014/05/07)
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- COMPOSITIONS AND METHODS FOR TREATING CANCER
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The instant invention provides a method of treating a cancer, selected from the group consisting of breast cancer, melanoma, colorectal cancer, non-small cell lung cancer and ovarian cancer, by administering a combination of a WEE1 inhibitor and a CHK1 inhibitor, wherein the WEE1 inhibitor is MK-1775 or a pharmaceutically acceptable salt thereof, or MK-3652 or a pharmaceutically acceptable salt thereof, and the CHK1 inhibitor is MK-8776 or a pharmaceutically acceptable salt thereof, or SCH900444 or a pharmaceutically acceptable salt thereof.
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Page/Page column 28
(2013/03/28)
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- POLYMORPH OF DIHYDROPYRAZOLOPYRIMIDINONE DERIVATIVE AS WEEL KINASE.INHIBITOR
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The present invention relates to the crystalline forms of 2-allyl-l -[6-(I -hydroxy- 1 methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-l-yl)phenyl]amino}-l,2-dihydro-3H- pyrazolo[3,4-d]pyrirnidin-3-one or a salt thereof, which are useful in the field of treatment of various cancers as a kinase inhibitor, especially as a Weel kinase inhibitor.
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Page/Page column 29-30
(2008/12/08)
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- Dihydropyrazolopyrimidinone derivatives
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The invention relates to compounds of a general formula (I): wherein Ar1 is an optionally-substituted aryl or heteroaromatic group; R1 is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R3 is a hydrogen atom or a lower alkyl group; R4 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of —N(R1k)R1m; T and U are a nitrogen atom or a methine group, etc. The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.
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Page/Page column 51
(2008/06/13)
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