H N H N X2 X1 R Example Flex-Hets X1 = O or S X2 = O or S R = NO2, CO2CH3, CO2Et Flexible Heteroarotinoids or Flex-Hets are class of small molecule drugs protected by a US Composition of Matter Patent No. 6,586,460 Heteroarotinoids containing urea or thiourea linker (Click on this link to acces). This patent protects Flex-Hets for prevention and treatment of a variety of diseases including cancer. An additional US Patent 7,612,107 Treatment and Inhibition of Disease Conditions Using Flexible Heteroarotinoids (Click on this link to access) extends the coverage for application of Flex-Hets for treatment of Polycystic Kidney Disease (PKD), the most common genetic mutation in the US. Click on the patents above to access their records. H N S H N S NO 2 SHetA2 (NSC 721689) SHetA2 also called NSC 721689 is the Lead Flex-Het Compound that is about to enter clinical trials. It was developed from structure-activity-relationship studies to maximize the cancer killing activity and minimize the toxicity of heteroarotinoids. Millions of dollars were expended for the pre-clinical testing of SHetA2 by several grants awarded to Doris M. Benbrook by the US National Cancer Institute (NCI)(Rapid Access to Intervention Development (RAID), Rapid Access to Preventive Intervention Development (RAPID), an Investigator Initiated R01).. These extensive studies demonstrated cancer therapeutic and chemoprevention activity in vitro1-9 and in vivo4,8,10,11, lack of mutagenicity or teratogenicity12,13, no toxicity14 and a pharmacologic profile suitable for an oral chemoprevention agent14-16. A pre-Investigational New Drug (IND) meeting report (PIND #121262) from the US Food and Drug Administration (US FDA) listed no obstacles for our moving forward to a Phase 0 Clinical trial in healthy individuals. Grants are currently under review to fund Phase 0 Clinical trials of SHetA2 for Chemoprevention of Ovarian Cancer in Healthy Individuals and Treatment of Cervical Cancer Patients. Peer-Reviewed Publications Cited. Click on Citation to Access PubMed Record. 1. 2. Benbrook DM, Lightfoot S, Ranger-Moore J, Liu T, Chengedza S, Berry WL, Dozmorov I. Karyometric and Gene Expression Analysis in an Organotypic Model of Endometrial Carcinogenesis and Chemoprevention. Gene Regulation and Systems Biology. 2008;2:21-42. PMID:19784388 Guruswamy S, Lightfoot S, Gold M, Hassan R, Berlin KD, Ivey RT, Benbrook DM. Effects of retinoids on cancerous phenotype and apoptosis in organotypic culture of ovarian carcinoma. Journal of the National Cancer Institute. 2001;93:516-525. PMID:11287445 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Chengedza S, Benbrook DM. NF-B is involved in SHetA2 circumvention of TNF- resistance, but not induction of intrinsic apoptosis. Anti-Cancer Drugs. 2010;21:297-305. PMID:20032777 Liu T, Masamha CP, Chengedza S, Berlin KD, Lightfoot S, He F, Benbrook DM. Development of flexible-heteroarotinoids for kidney cancer. Molecular Cancer Therapeutics. 2009;8(5):1227-1238. PMID:19417155 Liu T-Z, Hannafon B, Gill L, Kelly B, Benbrook DM. Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria. Molecular Cancer Therepeutics. 2007;6:1814-1822. PMID:17575110 Masamha CP, Benbrook DM. Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. Cancer Research. 2009;69(16):6565-6572. PMID:19638577 Myers T, Chengedza S, Lightfoot S, Pan Y, Dedmond D, Cole L, Tang Y, Benbrook DM. Flexible Heteroarotinoid (Flex-Het) SHetA2 inhibits angiogenesis in vitro and in vivo. Investigational New Drugs. 2008;27:304-318. PMID:18802666 Naylor M, Thompson DM, Lightfoot S, Benbrook DM. Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer. Journal of Cancer Therapy. 2013;4:7-19. Moxley KC, S., Mangiaracina (Benbrook), D. Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents. Gynecologic Oncology. 2009;115:438-442. PMID:19804900 Benbrook DM, Guruswamy S, Wang Y, Sun Z, Mohammed A, Zhang Y, Li Q, Rao CV. Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCmin/+ Mice By SHetA2 (NSC721689) without Toxicity. Cancer Prevention Research. 2013;6(9):908916. PMID:23852423 Benbrook D, Kamelle S, Guruswamy S, Lightfoot S, Rutledge T, Gould N, Hannafon B, Dunn ST, Berlin KD. Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists. Investigational New Drugs. 2005;23(5):417-428. PMID:23852423 Doppalapudi RS, Riccio ES, Davis Z, Menda S, Wang A, Du N, Green C, Kopelovich L, Rao CV, Benbrook DM, Kapetanovic IM. Genotoxicity of the cancer chemopreventive drug candidates CP-31398, SHetA2, and phospho-ibuprofen. Mutation Research. 2012;746(1):78-88. PMID: 22498038 Mic FA, Molotkov A, Benbrook DM, Duester G. Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis. . Proceedings of the National Academy of Sciences of the United States of America. 2003;100:7135-7140. PMID:12782789 Kabirov KK, Kapetanovic IM, Benbrook DM, Dinger N, Mankovskaya I, Zakharov A, Detrisac C, Pereira M, Martín-Jiménez T, Onua E, Banerjee A, van Breemen RB, Nikolić D, Chen L, Lyubimov AV. Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs. Drug and Chemical Toxicology. 2012;36(3):284-295. PMID: 22947079 Zhang Y, Hua Y, Benbrook DM, Covey JM, Dai G, Liu Z, Chan KK. High performance liquid chromatographic analysis and preclinical pharmacokinetics of the heteroarotinoid antitumor agent, SHetA2. Cancer Chemotherapy & Pharmacology. 2006;58(5):561-569. PMID:16534614 Liu Z, Zhang Y, Hua YF, Covey JM, Benbrook DM, Chan KK. Metabolism of a sulfurcontaining heteroarotionoid antitumor agent, SHetA2, using liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry. 2008;22(21):3371-3381. PMID:18837006