Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer... more Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer. While there are a significant number of clinically approved inhibitors of protein Tyr kinases, there are no drugs specifically targeting protein Tyr phosphatases in clinical use despite the attractiveness of the molecular target. This review examines the investigational challenges in identifying Tyr phosphatase inhibitors using the oncogenic phosphatase PTP4A3 as a prototype. The article includes a review of the structure, functionality and validation of PTP4A3 as a cancer target. It also provides an evaluation of existing small molecule and antibody inhibitors and provides new computational guidance for potentially more potent small molecule inhibitors. Tyr phosphatases, like PTP4A3, represent high value but ignored molecular targets for the treatment of cancer and other diseases. Although phosphatases are challenging targets, it seems likely that drug-like inhibitors of this important enzyme family would complement the growing number of protein Tyr kinase inhibitors. Animal models are beginning to provide validation for PTP4A3 as a molecular target for cancer progression and metastasis. The authors posit that greater efforts should be directed towards identifying Tyr phosphatase inhibitors for lead optimization and tool compounds to assist in interrogating and validating phosphatase involvement in physiological and pathological processes.
IntroductionAnimal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) imp... more IntroductionAnimal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) impairs neutrophil (PMN) recruitment in inflammation; in humans, MMP8 has been associated with inflammation. We hypothesized that septic patients with single nucleotide polymorphisms (SNPs) in the MMP8 promoter region will have a survival advantage, and this advantage is due to differences in MMP8 enzymatic activity and not MMP8 levels.MethodsWe examined data from patients with CAP-associated sepsis (GenIMS), analyzed three functional SNPs (rs3765620, rs1940475, rs11225395) in 1,567 Caucasians and tested associations with 60-day and 90-day mortality and severe sepsis incidence. We simulated functional MMP8 SNPs using anisotropic network modeling. Modeling suggested pro-domain structural stability affecting zymogen activation. Based upon the predictions, we then studied zymogen activation using bioluminescent resonance energy transfer (BRET). We generated recombinant pro-MMP8 with a pro-domain
Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer... more Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer. While there are a significant number of clinically approved inhibitors of protein Tyr kinases, there are no drugs specifically targeting protein Tyr phosphatases in clinical use despite the attractiveness of the molecular target. This review examines the investigational challenges in identifying Tyr phosphatase inhibitors using the oncogenic phosphatase PTP4A3 as a prototype. The article includes a review of the structure, functionality and validation of PTP4A3 as a cancer target. It also provides an evaluation of existing small molecule and antibody inhibitors and provides new computational guidance for potentially more potent small molecule inhibitors. Tyr phosphatases, like PTP4A3, represent high value but ignored molecular targets for the treatment of cancer and other diseases. Although phosphatases are challenging targets, it seems likely that drug-like inhibitors of this important enzyme family would complement the growing number of protein Tyr kinase inhibitors. Animal models are beginning to provide validation for PTP4A3 as a molecular target for cancer progression and metastasis. The authors posit that greater efforts should be directed towards identifying Tyr phosphatase inhibitors for lead optimization and tool compounds to assist in interrogating and validating phosphatase involvement in physiological and pathological processes.
IntroductionAnimal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) imp... more IntroductionAnimal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) impairs neutrophil (PMN) recruitment in inflammation; in humans, MMP8 has been associated with inflammation. We hypothesized that septic patients with single nucleotide polymorphisms (SNPs) in the MMP8 promoter region will have a survival advantage, and this advantage is due to differences in MMP8 enzymatic activity and not MMP8 levels.MethodsWe examined data from patients with CAP-associated sepsis (GenIMS), analyzed three functional SNPs (rs3765620, rs1940475, rs11225395) in 1,567 Caucasians and tested associations with 60-day and 90-day mortality and severe sepsis incidence. We simulated functional MMP8 SNPs using anisotropic network modeling. Modeling suggested pro-domain structural stability affecting zymogen activation. Based upon the predictions, we then studied zymogen activation using bioluminescent resonance energy transfer (BRET). We generated recombinant pro-MMP8 with a pro-domain
Uploads
Papers by Ahmet Bakan