KM 11060

KM11060 is a novel corrector of the F508del-CFTR trafficking defect. Target: CFTR in vitro: Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics. KM11060 rescues F508del-CFTR trafficking in cultured cells and native epithelial tissues. KM11060 partially corrects F508del-CFTR processing and increases surface expression to 75% of that observed in cells incubated at low temperature. Up to 50% of the F508del-CFTR in cells treated with KM11060 was complex-glycosylated, indicating passage through the Golgi. KM11060 as a promising compound for further development of CF therapeutics. [1] in vivo: In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. [2]

References:
[1]. Robert R, et al. Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol. 2008 Feb;73(2):478-89. [2]. Wu H, et al. Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice. PLoS One. 2014 Mar 26;9(3):e93003.

Osteobiographic analysis of skeleton I, Sitio Toca dos Coqueiros, Serra da Capivara National Park, Brazil, 11,060 BP: first results.[Pubmed:12012362]

Am J Phys Anthropol. 2002 Jun;118(2):99-110.

This paper presents an osteobiographic analysis of a single skeleton found in a small rock shelter known as Toca dos Coqueiros, Piaui, Brazil. This find is of interest because of an exceptionally old radiocarbon date associated with it. The date (11,060 BP) was obtained from charcoal associated directly with the skeleton. This is an interesting find because of the rarity of osteobiographic studies of skeletons of such antiquity. Despite the existence of two projectile points in association with the burial, the morphological and molecular analyses of the skeleton demonstrated that this was a female. She was about 35-45 years of age at death. The skeleton exhibited acute and chronic bone lesions. Oral pathology was also observed, including an interproximal dental groove, probably caused by the therapeutic use of a cactus thorn. This could be one of the oldest cases of an analgesic plant used in the prehistoric Americas.

Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect.[Pubmed:17975008]

Mol Pharmacol. 2008 Feb;73(2):478-89.

The F508del mutation impairs trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) to the plasma membrane and results in a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. We recently used a novel high-throughput screening (HTS) assay to identify small-molecule correctors of F508del CFTR trafficking and found several classes of hits in a screen of 2000 compounds (Carlile et al., 2007). In the present study, we have extended the screen to 42,000 compounds and confirmed sildenafil as a corrector using this assay. We evaluated structural analogs of sildenafil and found that one such molecule called KM11060 (7-chloro-4-{4-[(4-chlorophenyl) sulfonyl] piperazino}quinoline) was surprisingly potent. It partially restored F508del trafficking and increased maturation significantly when baby hamster kidney (BHK) cells were treated with 10 nM for 24 h or 10 muM for 2 h. Partial correction was confirmed by the appearance of mature CFTR in Western blots and by using halide flux, patch-clamp, and short-circuit current measurements in unpolarized BHK cells, monolayers of human airway epithelial cells (CFBE41o(-)), and intestines isolated from F508del-CFTR mice (Cftr(tm1Eur)) treated ex vivo. Small-molecule correctors such as KM11060 may serve as useful pharmacological tools in studies of the F508del-CFTR processing defect and in the development of cystic fibrosis therapeutics.