The pharmacological parameters, such as oral absorp tion, and compound solubility remains to be overcome by further modifications to the core structure and ex ploration of dosing formulations through the efforts of medicinal chemists and formulation experts. The safety of TAI 1 was evaluated with activity in nor mal cell lines, hERG inhibition and a pilot toxicity study. The activity in normal cell lines suggests that TAI 1 has high cancer cell specificity and a high therapeutic index. In combination with hERG inhibition assay, the in vitro evaluation shows that TAI 1 is safe as an anticancer agent with little liability on cardiac toxicity. Further more, in vivo toxicity studies in the same species of mice as the xenograft studies showed no body weight loss and no changes in organ weight and plasma indices.

These athymic mice used for in vivo modeling were good cor relation of the toxicity incurred at efficacy doses in the xenograft models, but were unable to show immunosup pression, a common side effect of chemotherapeutics. In rodent selleck chemicals with intact thymus, dosing of TAI 1 lead to a dose dependent decrease of thymus weights and a slight decrease of spleen weights, but did not showed dose dependent changes in blood indices, including white blood cells, due to TAI 1. It should be noted that it is also possible that the lack of body weight loss and hematological effects may not be evident in only 7 days, and toxicity studies dosed for longer period of times may be able to further determine the long term effects of TAI 1.

In contrast to the 7 day toxicity study conducted WIKI4 c-Met inhibitor independently of the xenograft studies in SCID mice, xenograft studies seemed to show a modest body weight loss during dosing. Since this effect was not evi dent in the independently conducted toxicity studies in the same species of mice, the body weight loss is suggested to be nonspecific to the compound. The body weight loss may be related to the tumor burden or different tumor xenograft interactions, since the change varied between models. The influencing factors of body weight loss in the xenograft models re mains unclear, and further parallel designs of xenograft and toxicity studies may help determine the underlying cause. The translational implications were further explored with studies in multi drug resistant cell lines, synergistic studies, and clinical databases. The activity in MDR cell lines was shown with other Hec1 analogues and is not specific to the Hec1 analogue TAI 1. The activity in MDR cell lines carry important clinical implications and suggests that Hec1 targeted agents may be able to offered as a treatment option to cancer patients who do not respond to currently available anticancer agents, a major clinical advance.