Compound 3a, DV2-103, is a kinase inactive analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both compounds, 2 and 3a, are known to reduce production of beta amyloid (Aβ) peptide in cells and animal models. We have now prepared and evaluated a series of PD-173955 analogues, several of which reduced Aβ production potently. This occurs in cells expressing human full-length amyloid precursor protein (APP) and not in cells expressing APP β-C terminal fragment (APP-C99), suggesting that the kinase inactive analogues strongly affect β-secretase (BACE1) cleavage of APP, similarly to Gleevec. A combination of the kinase inactive analogues of PD173955 with a BACE1 inhibitor (BACEi), namely, BACE IV, strongly reduced Aβ levels in cells, as noted previously with Gleevec and analogues. Several potent compounds also penetrated and accumulated in mouse brain in high nanomolar to low micromolar concentration.

01 Sep 2013·Vascular PharmacologyQ3 · MEDICINE

Propionyl-L-carnitine induces eNOS activation and nitric oxide synthesis in endothelial cells via PI3 and Akt kinases

Q3 · MEDICINE

Article

Author: Kan Zhao ; Wen-hu Ning

Propionyl-l-carnitine (PLC) is a natural short-chain derivative of l-carnitine (LC), a natural amino acid that plays an important role in fatty acid metabolism. Recent studies suggest that PLC has vascular protective effects. Because of the importance of endothelial nitric oxide synthase (eNOS) and its product, antiatherogenic molecule nitric oxide (NO), in vascular endothelial function, we sought to elucidate that if PLC would stimulate eNOS and its upstream activators Akt and phosphatidylinositol 3-kinase (PI3 Kinase) in cultured human aortic endothelial cells (HAEC). PLC caused eNOS phosphorylation at Ser-1177, and dominant negative Akt and a novel Akt-selective inhibitor MK-2206 inhibited both PLC-mediated phosphorylation and activation of the enzyme. PI3 kinase inhibition also blocked the phosphorylation and activation of eNOS by PLC. Studies with specific drug inhibitors PD173955 and PP2 showed that the non-receptor tyrosine kinase, src, is an upstream stimulator of the PI3 kinase-Akt pathway in this pathway. In addition, PLC significantly decreased intracellular ATP/ADP ratio and activate AMPK, subsequently leading to Src activation. Finally, we demonstrated that the effects of PLC to augment eNOS activity were associated with a net increase in NO release from endothelial cells. NO production following incubation with PLC was abolished in endothelial cells coincubated with L-NAME, PD173955, LY294002, MK-2206 and compound C. In conclusion, PLC, via AMPK/Src-mediated signaling that leads to activation of PI3 kinase and Akt, stimulates eNOS, leading to increased production of NO.

01 Sep 2010·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

New effective inhibitors of the Abelson kinase

Q3 · MEDICINE

Article

Author: George A. Kraus ; Marjan Mokhtarian ; Marit Nilsen-Hamilton ; Samir Mehanovic ; Vinayak Gupta

The effects of substituents on the aryl ring were studied by the preparation and testing of several PD173955 analogs. Inserting a single carbon atom into the C-N bond in the aniline subunit (PDC) reduced the kinase inhibition by a factor of 200. Despite its decreased affinity for Abl compared with PD173955, PDC exhibits a Ki very similar to that reported for Imatinib. Increased water solubility is also gained by replacing the thiomethyl group with an amino or glycyl moiety. For both PD173955 and PDC, the analogs with amino groups in place of the methylthio group are 10 times more inhibitory than the parent molecules. Two molecules were identified with Kis about three orders of magnitude lower than reported for Imatinib.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	US	Pfizer Inc.	-
Breast Cancer	Preclinical	US	Memorial Sloan Kettering Cancer Center	15 Dec 1999
Colonic Cancer	Preclinical	US	Memorial Sloan Kettering Cancer Center	15 Dec 1999

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