Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potential Antitumor Agents. 1. Synthesis and Structure–Activity Relationships

Vanotti, Ermes; Amici, Raffaella; Bargiotti, Alberto; Berthelsen, Jens; Bosotti, Roberta; Ciavolella, Antonella; Cirla, Alessandra; Cristiani, Cinzia; D’Alessio, Roberto; Forte, Barbara; Isacchi, Antonella; Martina, Katia; Menichincheri, Maria; Molinari, Agnese; Montagnoli, Alessia; Orsini, Paolo; Pillan, Antonio; Roletto, Fulvia; Scolaro, Alessandra; Tibolla, Marcellino; Valsasina, Barbara; Varasi, Mario; Volpi, Daniele; Santocanale, Corrado

doi:10.1021/jm700956r

Cited by 84 publications

(72 citation statements)

References 19 publications

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“…Recently, some small molecule inhibitors of Cdc7 kinase activity have been developed and are being tested in clinical trials as candidate anti-cancer drugs (Ito et al 2008;Montagnoli et al 2008;Vanotti et al 2008;Ermoli et al 2009). …”

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confidence: 99%

ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

et al. 2013

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Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosome Cdh1 (APC/C Cdh1 ) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C Cdh1 through degradation of Cdh1 upon replication block, thereby stabilizing APC/C Cdh1 substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase h. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse under conditions of replication stress.

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ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

et al. 2013

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“…However, the hydrogen (5), methyl (6−8), cyano (12−14), and carboxamide (15) substitutions led to varied degrees of erosion on the Cdc7 inhibitory activity. Understanding of ligand binding to Cdc7 kinase is based on published structural studies 16,18,19,25 of compounds 2−4 using surrogates. Attempts to crystallize Cdc7 have not been successful to date, so structural information derives from either crystallographic studies of ligand-bound surrogate kinases, such as PIM or GSK3β kinases, or ligand docking into homology models of Cdc7 kinase.…”

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confidence: 99%

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195

Tong

Stewart

Florjancic

et al. 2013

ACS Med. Chem. Lett.

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To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.

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“…A series of pyrrolopyridinone compounds with potent activity against Cdc7 has been reported by Nerviano Medical Sciences (Montagnoli et al 2008a;Vanotti et al 2008). PHA-767491 (#1) was identifi ed from high throughput screening (HTS) and characterized as an ATP-competitive inhibitor of Cdc7 (IC 50 = 10 nM).…”

Section: Emerging Cdc7 Kinase Inhibitorsmentioning

confidence: 99%

Drug design with Cdc7 kinase: a potential novel cancer therapy target

Sawa¹,

Masai²

2008

DDDT

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Identifi cation of novel molecular targets is critical in development of new and effi cient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not signifi cantly affect viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC 50 of less than 10 nM have been identifi ed, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy.

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Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potential Antitumor Agents. 1. Synthesis and Structure–Activity Relationships

Cited by 84 publications

References 19 publications

ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195

Drug design with Cdc7 kinase: a potential novel cancer therapy target

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Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potential Antitumor Agents. 1. Synthesis and Structure–Activity Relationships

Cited by 84 publications

References 19 publications

ATR–Chk1–APC/CCdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

ATR–Chk1–APC/CCdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195

Drug design with Cdc7 kinase: a potential novel cancer therapy target

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ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress