Cancer is the second most common cause of death in the United States, exceeded only by heart disease. In the United States, cancer accounts for 1 of every 4 deaths. The 5-year relative survival rate for all cancers patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977 (Cancer Facts & Figures American Cancer Society: Atlanta, Ga. (2008)). This improvement in survival reflects progress in diagnosing at an earlier stage and improvements in treatment. Discovering highly effective anticancer agents with low toxicity is a primary goal of cancer research.
Prostate cancer is one of the most frequently diagnosed noncutaneous cancers among men in the US and is the second most common cause of cancer deaths with over 180,000 new cases and almost 29,000 deaths expected this year. Patients with advanced prostate cancer undergo androgen deprivation therapy (ADT), typically either by luteinizing hormone releasing hormone (LHRH) agonists or by bilateral orchiectomy. Androgen deprivation therapy not only reduces testosterone, but estrogen levels are also lower since estrogen is derived from the aromatization of testosterone, which levels are depleted by ADT. Androgen deprivation therapy-induced estrogen deficiency causes significant side effects which include hot flushes, gynecomastia and mastalgia, bone loss, decreases in bone quality and strength, osteoporosis and life-threatening fractures, adverse lipid changes and higher cardiovascular disease and myocardial infarction, and depression and other mood changes.
Malignant melanoma is the most dangerous form of skin cancer, accounting for about 75% of skin cancer deaths. The incidence of melanoma is rising steadily in Western populations. The number of cases has doubled in the past 20 years. Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and Caucasians. According to a WHO Report, about 48,000 melanoma-related deaths occur worldwide per year.
Currently there is no effective way to treat metastatic melanoma. It is highly resistant to current chemotherapy, radiotherapy, and immunotherapy. Metastatic melanoma has a very poor prognosis, with a median survival rate of 6 months and a 5-year survival rate of less than 5%. In the past 30 years, dacarbazine (DTIC) is the only FDA-approved drug for metastatic melanoma. However, it provides only less than 5% of complete remission in patients. In recent years, great efforts have been attempted in fighting metastatic melanoma. Neither combinations of DTIC with other chemotherapy drugs (e.g., cisplatin, vinblastine, and carmustine) nor adding interferon-α2b to DTIC have shown a survival advantage over DTIC treatment alone. Most recently, clinical trials with antibodies and vaccines to treat metastatic melanoma also failed to demonstrate satisfactory efficacy. Ipilimumab (Yervoy) is such a drug that uses your immune system to fight melanoma. Ipilimumab is used to treat advanced melanoma that has spread beyond its original location. Targeted therapy uses medications designed to target specific vulnerabilities in cancer cells. Vemurafenib (Zelboraf) is a targeted therapy approved to treat advanced melanoma that cannot be treated with surgery or melanoma that has spread through the body. Vemurafenib only treats melanoma that has a certain genetic mutation.
Tubulin/microtubule-interacting drugs are used successfully for treatment of a wide variety of human cancers. They are commonly classified into two major categories: microtubule-stabilizing (e.g., taxanes, epothilones) and microtubule-destabilizing drugs (e.g., vinca alkaloids, colchicine). Three major binding sites on α,β-tubulin subunits have been identified as taxane-, vinca alkaloid- and colchicine-binding sites. While antimitotic agents interacting with the taxane- or vinca alkaloid-binding sites in tubulin are tremendously successful in clinical oncology, there are no Food and Drug Administration (FDA)-approved colchicine-binding site drugs currently available for cancer treatment. Most of the colchicine-binding agents have high potency, relatively simple chemical structures for optimization, selective toxicity towards tumor vasculature, and show promising ability to overcome P-glycoprotein (P-gp) efflux pump mediated multidrug resistance.
Several outstanding agents for such an approach are listed in FIG. 1. Combretastatin A-4 (CA-4) is the most active member of the combretastatins family, isolated from the African tree Combretum caffrum. CA-4 exhibits strong antitubulin activity by binding to the colchicine-site and has been the subject of Phase II and Phase III clinical studies. The replacement of the olefinic bridge of CA-4 with a carbonyl group yields phenstatin, which has similar potency and mechanisms of action with CA-4. BPR0L075 and Oxi-6196 are 2-aroylindole and dihydronaphthalene analogues of CA-4, which show strong inhibition on tubulin polymerization. Methylated chalcone SD400, which has an IC50 value of 0.21 nM against K562 human leukemia cells, is a potent tubulin inhibitor. Podophyllotoxin is a non-alkaloid toxin lignin, and it also possesses an anticancer property that can be attributed to the inhibition of tubulin polymerization through binding to the colchicine binding site. Accordingly, the colchicine-binding site compounds have attracted great interest from medicinal chemists in recent years.