Irreversible Protein Kinase Inhibitors: Balancing the Benefits and Risks

Barf, Tjeerd; Kaptein, Allard

doi:10.1021/jm3003203

Cited by 292 publications

(312 citation statements)

References 109 publications

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“…The emergence of secondary FGFR resistant mutations is comparable to that observed in response to ALK inhibitors in ALK-fusion patients (16), suggesting a strategic approach of developing structurally optimized FGFR inhibitors may be required for durable responses in FGFR-driven cancers. In this strategy, a covalent mechanism may be an advantage based on the assumption that covalent inhibitors exhibit less susceptibility to resistance arising from mutations (17).…”

Section: Discussionmentioning

confidence: 99%

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

Venetsanakos

Brameld

Phan

et al. 2017

Molecular Cancer Therapeutics

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An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors.

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Section: Discussionmentioning

confidence: 99%

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

Venetsanakos

Brameld

Phan

et al. 2017

Molecular Cancer Therapeutics

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“…Covalent inhibitors have been demonstrated to hold the promise in overcoming the challenges of potency, selectivity, efficacy, and resistance faced by noncovalent inhibitors (45)(46)(47). Currently, structure-based approaches are employed to design small molecules that target kinases through covalent attachment to a specific cysteine.…”

Section: Discussionmentioning

confidence: 99%

JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

et al. 2015

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Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue. Cancer Res; 75(22); 4923-36. Ó2015 AACR.

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“…Addition of groups at the ortho position (6−8) and para position (9−11) led to a decrease in LIMK2 activity. Small groups such as fluoro (12) and methyl (14) installed at the meta position did provide a slight improvement in activity, Unlike the limited SAR exhibited in Table 1, the tertiary amide on the left side of the molecule had a greater scope (Table 2). While the amide itself was irreplaceable, the benzyl group could be elaborated or replaced with a saturated ring system.…”

mentioning

confidence: 95%

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation

Goodwin

Cianchetta

Burgoon

et al. 2014

ACS Med. Chem. Lett.

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The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.

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Irreversible Protein Kinase Inhibitors: Balancing the Benefits and Risks

Cited by 292 publications

References 109 publications

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance

JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation

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