Development of an Expedient Process for the Multi-Kilogram Synthesis of Chk1 Inhibitor GDC-0425

Stumpf, Andreas; Cheng, Zhigang Ken; Wong, Brian A.; Reynolds, Mark; Angelaud, Rémy; Girotti, James; Deese, Alan; Gu, Christine; Gazzard, Lewis

doi:10.1021/acs.oprd.5b00105

Cited by 12 publications

(7 citation statements)

References 20 publications

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“…Very few information and biological data are available on these compounds, yet. 118 Among the biological targets reviewed herein, CHK1 is the one whose inhibition has been the most studied. Following the identification of seminal non-selective CHK1 inhibitors, several ATP-competitive inhibitors with improved CHK1 selectivity were developed.…”

Section: Chk1 Inhibitorsmentioning

confidence: 99%

ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells

et al. 2017

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DNA inevitably undergoes a high number of damages throughout the cell cycle. To preserve the integrity of the genome, cells have developed a complex enzymatic machinery aimed at sensing and repairing DNA lesions, pausing the cell cycle to provide more time to repair, or induce apoptosis if damages are too severe. This so-called DNA-damage response (DDR) is yet considered as a major source of resistance to DNA-damaging treatments in oncology. Recently, it has been hypothesized that cancer stem cells (CSC), a sub-population of cancer cells particularly resistant and with tumour-initiating ability, allow tumour re-growth and cancer relapse. Therefore, DDR appears as a relevant target to sensitize cancer cells and cancer stem cells to classical radio- and chemotherapies as well as to overcome resistances. Moreover, the concept of synthetic lethality could be particularly efficiently exploited in DDR. Five kinases play pivotal roles in the DDR: ATM, ATR, CHK1, CHK2 and WEE1. Herein, we review the drugs targeting these proteins and the inhibitors used in the specific case of CSC. We also suggest molecules that may be of interest for preclinical and clinical researchers studying checkpoint inhibition to sensitize cancer and cancer stem cells to DNA-damaging treatments.

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Section: Chk1 Inhibitorsmentioning

confidence: 99%

ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells

et al. 2017

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“…The oral CHK1 inhibitors GDC-0425 and GDC-0575 have been reported in phase I clinical trials. 16,17 There remains a clear need for highly selective oral CHK1 inhibitors from different chemical series to advance to clinical studies.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In addition, preclinical data on the emerging contexts for CHK1 monotherapy suggests that daily dosing may be needed, for which an oral drug would again be favored. The oral CHK1 inhibitors GDC-0425 and GDC-0575 have been reported in phase I clinical trials. , There remains a clear need for highly selective oral CHK1 inhibitors from different chemical series to advance to clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Osborne¹,

Matthews²,

McHardy³

et al. 2016

J. Med. Chem.

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Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

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“…Other aromatics ketoness uch as 2-acetonaphthone and benzophenone were suitablef or this reactiond elivering the reduced products with yields reaching 98 % ( Entries13a nd 14). Furthermore, an umber of aliphatic ketones were investigated (Entries [16][17][18][19].…”

mentioning

confidence: 99%

“…The synthesis of the later product is of relevance as it serves as ak ey intermediate in the productiono fG enentech 's GDC-0425 an inhibitor of ChK1 (Checkpoint Kinase 1) that is being currently investigated in clinicalp hase If or the treatment of cancer. [16] Noteworthy,d ihydro-b-ionone, an aliphatic ketone containing an alkene function, was reduced to the corresponding alcoholi n9 7% withouta ffecting the alkene moiety (Entry 19). Finally,t he catalytic system also promoted the reductiono fh eteroaromatic ketones (Entries20-23), although ah igher metal loading was required to achieve high conversions and excellent yields.…”

mentioning

confidence: 99%

Molecularly Defined Manganese Pincer Complexes for Selective Transfer Hydrogenation of Ketones

et al. 2016

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For the first time an easily accessible and well‐defined manganese N,N,N‐pincer complex catalyzes the transfer hydrogenation of a broad range of ketones with good to excellent yields. This cheap earth abundant‐metal based catalyst provides access to useful secondary alcohols without the need of hydrogen gas. Preliminary investigations to explore the mechanism of this transformation are also reported.

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Development of an Expedient Process for the Multi-Kilogram Synthesis of Chk1 Inhibitor GDC-0425

Cited by 12 publications

References 20 publications

ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells

ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Molecularly Defined Manganese Pincer Complexes for Selective Transfer Hydrogenation of Ketones

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