Anticancer Market in the United States. Medicines used by oncologists to treat the majority of solid tumors and various other cancers have not significantly changed in the last twenty years. In fact, the taxanes, platinums, nitrogen mustards, nucleoside analogues, anthracyclines, and camptothecins are all still first-line or primary therapies despite record increases in R&D spending by the National Institutes of Health and the pharmaceutical industry. Even though a handful of newer anticancer therapies have extended overall survivals in patients with certain solid tumors, they were approved to be administered with the existing older chemotherapies because they were inferior as monotherapies. Based upon American Society of Clinical Oncology (ASCO) presentations from 2005 to 2012, nothing is currently in clinical development that has a chance of replacing these older chemotherapies as first-line treatments for the majority of solid tumors. This historical evidence illustrates the roadblocks that have been encountered in anticancer research and provides insights to our scientific limitations.
Historically, insurmountable challenges in human health have been solved by great discoveries inspired from the chemistry of natural products. Natural products chemistry has shaped the pharmaceutical industry and still dominates global prescriptions for bacterial infections, elevated cholesterol, parasitic infections, pain, cancer, malaria, and pulmonary diseases; diabetes is soon to be added to this list. Unfortunately, amid the fervor over the possibilities of combinatorial chemistry and highly targeted therapy, nature’s chemistry has been neglected over the last twenty years. Now as it is becoming clear that these new technologies aren’t a silver bullet and that chemical diversity is still needed to tackle complex targets, drug discovery should once again embrace natural products. Fortunately, natural products chemists including Sequoia have remained dedicated to applying modern tools to uncovering new chemistry present in miniscule quantities in plants. We can thus discover a diversity of new chemistry that would have seemed impossible twenty years ago. It is this chemistry from nature that will inspire the next advance in anticancer treatments.
Sequoia's Anticancer Program. Sequoia is developing an anticancer compound (SQ1274) for use against solid tumors including ovarian and lung cancer. SQ1274 is a chemically synthesized variant of a new compound discovered using our platform technology (Isolation and Identification of the Novel Tubulin Polymerization Inhibitor Bifidenone, R.B. Williams, et al, Journal of Natural Products, Article ASAP, DOI: 10.1021/acs.jnatprod.6b00893). Its molecuar weight is <400, and its chemical scaffold is novel to drug discovery and development. SQ1274 is a tubulin inhibitor active against over 50 human cancer cell lines, including several taxane-resistant cell lines. Its average IC50 is 26 nM against 53 cell lines from cancers including ovarian, lung, breast, colon, CNS, melanoma, prostate, renal, and uterine. It is 5-1000 times more active than paclitaxel in ten of these lines. SQ1274 has demonstrated efficacy in multiple mouse xenograft models in three independent laboratories using human cell lines from lung, skin, brain, and blood. Dog studies have demonstrated that SQ1274’s dosing schedule provides greater systemic exposure than achieved by docetaxel. Preliminary studies also suggest that it is less neurotoxic than docetaxel. Based on preclinical evidence, SQ1274 appears superior to other candidates under development for the treatment of patients with solid tumors. Sequoia is completing the IND-enabling preclinical safety studies, and anticipates that SQ1274 will enter clinical trials in 2018.