Summary: Steroids containing the fundamental tetracyclic unit with no methyl groups at C-10 and C-13 and with no side chain at C-17. The concept includes both saturated and unsaturated derivatives.

Top Publications

  1. Ihle N, Williams R, Chow S, Chew W, Berggren M, Paine Murrieta G, et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther. 2004;3:763-72 pubmed
    ..PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment. ..
  2. Hong D, Bowles D, Falchook G, Messersmith W, George G, O Bryant C, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18:4173-82 pubmed publisher
  3. Okuda K, Korzekwa A, Shibaya M, Murakami S, Nishimura R, Tsubouchi M, et al. Progesterone is a suppressor of apoptosis in bovine luteal cells. Biol Reprod. 2004;71:2065-71 pubmed
    ..01). The overall results indirectly show that intraluteal P4 suppresses apoptosis in bovine luteal cells through the inhibition of Fas and caspase-3 mRNA expression and inhibition of caspase-3 activation...
  4. Ihle N, Paine Murrieta G, Berggren M, Baker A, Tate W, Wipf P, et al. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther. 2005;4:1349-57 pubmed
    ..Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition. ..
  5. Chabbert Buffet N, Meduri G, Bouchard P, Spitz I. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005;11:293-307 pubmed
    ..Further developments might also include hormone replacement therapy in post-menopausal women, as well as the treatment of hormone-dependent tumours. ..
  6. Koul D, Shen R, Kim Y, Kondo Y, Lu Y, Bankson J, et al. Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol. 2010;12:559-69 pubmed publisher
    ..Our studies affirm that the PI3K pathway is a highly specific molecular target for therapies for glioblastoma and other cancers with aberrant PI3K/PTEN expression. ..
  7. Nodera H, Kaji R. [Pathophysiology and new treatment for hereditary neuropathy]. No To Shinkei. 2004;56:761-70 pubmed
  8. Sun D, Bhanu Prasad B, Schuber P, Peng Z, Maxwell D, Martin D, et al. Improved synthesis of 17?-hydroxy-16?-iodo-wortmannin, 17?-hydroxy-16?-iodoPX866, and the [(131)I] analogue as useful PET tracers for PI3-kinase. Bioorg Med Chem. 2013;21:5182-7 pubmed publisher
    ..The differences between wortmannin and its iodo analogue were compared by covalently docking each structure to L833 in PI3K. ..
  9. Cameron S, Glasier A, Narvekar N, Gebbie A, Critchley H, Baird D. Effects of onapristone on postmenopausal endometrium. Steroids. 2003;68:1053-9 pubmed
    ..The antiprogestin onapristone, in contrast to mifepristone, is not agonistic on postmenopausal endometrium and does not exert obvious antiproliferative effects. It does however cause a dose dependent suppression of FSH and LH release. ..

More Information


  1. Lin V, Aw S, Ng E, Tan M. Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues. Br J Cancer. 2001;85:1978-86 pubmed
    ..In any case, undesired side effects of antiprogestin may create clinical complications. PR-transfected MDA-MB-231 breast cancer cells provide a model for studying the functions of progesterone analogues. ..
  2. Ihle N, Lemos R, Schwartz D, Oh J, Halter R, Wipf P, et al. Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther. 2009;8:94-100 pubmed publisher
  3. Nishino T, Ishibashi K, Hirtreiter C, Nishino Y. The prostate growth stimulation by progesterone is due to androgenic products and progesterone receptor-mediated mechanisms. Pharmazie. 2009;64:587-9 pubmed
    ..These findings suggest that the stimulatory effect of P4 on the rat DLP may be partly due to androgenic products derived from P4 and may be also mediated by PR. ..
  4. Sarkar N. The state-of-the-art of emergency contraception with the cutting edge drug. Ger Med Sci. 2011;9:Doc16 pubmed publisher
    ..Thus, ulipristal acetate goes one-step ahead of levonorgestrel in the field of emergency contraception treatment. Further studies are needed to explore the potential of other SPRMs to be cutting edge emergency contraceptive drugs. ..
  5. Khan J, Amazit L, Bellance C, Guiochon Mantel A, Lombes M, Loosfelt H. p38 and p42/44 MAPKs differentially regulate progesterone receptor A and B isoform stabilization. Mol Endocrinol. 2011;25:1710-24 pubmed publisher
    ..Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis. ..
  6. Yuan Y, Yang X, Li W, Zheng X, Gu R, Yu Y. [Subcellular proteomic analysis of Tetrazanbigen on human hepatocellular carcinoma cell line QGY-7701]. Zhonghua Gan Zang Bing Za Zhi. 2011;19:908-11 pubmed publisher
    ..05, 95% CI 1.005-2.121) were independent predictors for OS of advanced HCC. Cryoablation treatment can prolong median OS and TTP of advanced HCC. ECOG PS and ALCPS are important predictors for survival time of advanced HCC. ..
  7. Resuehr D, Glore D, Taylor H, Bruner Tran K, Osteen K. Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Fertil Steril. 2012;98:948-56.e1 pubmed publisher
    ..We demonstrate for the first time that acute TCDD exposure disrupts cannabinoid signaling in the human endometrium. ..
  8. Woźny M, Brzuzan P, Luczyński M, Góra M, Bidzińska J, Jurkiewicz P. Effects of cyclopenta[c]phenanthrene and its derivatives on zona radiata protein, ERalpha, and CYP1A mRNA expression in liver of rainbow trout (Oncorhynchus mykiss Walbaum). Chem Biol Interact. 2008;174:60-8 pubmed publisher
    ..5-fold; P<0.05). The finding that ZEA is capable of acting as either estrogenic and xenobiotic compound, should be further explored in a more detailed and differently designed experiment. ..
  9. Winneker R, Fensome A, Zhang P, Yudt M, McComas C, Unwalla R. A new generation of progesterone receptor modulators. Steroids. 2008;73:689-701 pubmed publisher
    ..Finally, as the biology of the PR becomes further defined, we speculate on the future development of novel PR modulators. ..
  10. Williams R, Baker A, Ihle N, Winkler A, Kirkpatrick L, Powis G. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother Pharmacol. 2006;58:444-50 pubmed
    ..Hair offers a way of measuring the effects of PI-3-K signaling inhibitors and, in cancer patients, may provide a readily obtainable surrogate tissue for assessing PI-3-K and phospho-Akt inhibition in tumor. ..
  11. Nishino T, Ishibashi K, Hirtreiter C, Nishino Y. Potentiation of the antitumor effect of tamoxifen by combination with the antiprogestin onapristone. J Steroid Biochem Mol Biol. 2009;116:187-90 pubmed publisher
    ..These data clearly suggest the sense of a combination of TAM with an antiprogestin in breast cancer treatment. ..
  12. Marx S, Wentz M, MacKay L, Schlembach D, Maul H, Fittkow C, et al. Effects of progesterone on iNOS, COX-2, and collagen expression in the cervix. J Histochem Cytochem. 2006;54:623-39 pubmed
    ..456; p=0.03). Progesterone prolonged pregnancy, decreasing the iNOS and COX-2 mRNA (p=0.036). In conclusion, there may be an interaction between the nitric oxide and prostaglandin pathways in cervical ripening and parturition. ..
  13. Bradbury J. Antiprogesterone hope for inherited neuropathy. Lancet Neurol. 2004;3:6 pubmed
  14. Asem E, Conkright M. Role of progesterone in luteinizing hormone-induced fibronectin production and deposition by chicken granulosa cells in vitro. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1995;112:247-55 pubmed
    ..They indicate that LH-stimulated fibronectin production and deposition by chicken granulosa cells is mediated (at least in part) by progesterone. ..
  15. Suarez V, Park E, Hankins G, Soloff M. Expression of regulator of G protein signaling-2 in rat myometrium during pregnancy and parturition. Am J Obstet Gynecol. 2003;188:973-7 pubmed
  16. Kraml J, Kolinska J, Sinkora J, Zakostelecka M, Kadlecová L, Hirsová D, et al. Glucocorticoid agonistic and antagonistic effects of mifepristone and onapristone on thymocyte subset composition and CD26/dipeptidyl peptidase IV activity in infant male rats. J Steroid Biochem Mol Biol. 2003;87:85-96 pubmed
  17. Maggi R, Pimpinelli F, Casulari L, Piva F, Martini L. Antiprogestins inhibit the binding of opioids to mu-opioid receptors in nervous membrane preparations. Eur J Pharmacol. 1996;301:169-77 pubmed
    ..These results indicate that RU-486 may interact with brain mu-opioid receptors in vitro, by decreasing the affinity of opioid ligands. ..
  18. Oh S, Yedidag E, Bielefeldt K. Differential effects of progesterone and its analogues on the contractility of the murine jejunum in vitro. J Surg Res. 1998;75:1-5 pubmed
    ..Rather, they suggest a specific interaction between the steroid hormone and a still unidentified protein that differs in its function and pharmacological profile from the known progesterone receptor. ..
  19. Robertson J, Willsher P, Winterbottom L, Blamey R, Thorpe S. Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer. Eur J Cancer. 1999;35:214-8 pubmed
    ..Transient liver function test abnormalities developed in a number of patients, mainly during the first 6 weeks of treatment. In conclusion Onapristone can induce tumour responses in human breast cancer. ..
  20. Rueda B, Hendry I, Hendry III W, Stormshak F, Slayden O, Davis J. Decreased progesterone levels and progesterone receptor antagonists promote apoptotic cell death in bovine luteal cells. Biol Reprod. 2000;62:269-76 pubmed
    ..Interestingly, there was no difference (P >/= 0.05) in P(4) levels after treatment with PR antagonists. These observations support the concept that P(4) represses the onset of apoptosis in the CL by a PR-dependent mechanism. ..
  21. Hyder S, Chiappetta C, Stancel G. Induction of the angiogenic factor VEGF in the uterus by the antiprogestin onapristone. Cancer Lett. 2000;156:101-7 pubmed
  22. Parmar T, Nimbkar Joshi S, Katkam R, Gadkar Sable S, Chaudhari U, Manjramkar D, et al. Differential expression of calreticulin, a reticuloplasmin in primate endometrium. Hum Reprod. 2009;24:2205-16 pubmed publisher
    ..These novel data open up new lines of investigation for elucidating the mechanisms by which hormones or embryonic stimuli influence the sub-cellular physiology of endometrium. ..
  23. Miner J, Tyree C, Hu J, Berger E, Marschke K, Nakane M, et al. A nonsteroidal glucocorticoid receptor antagonist. Mol Endocrinol. 2003;17:117-27 pubmed
    ..Once bound, however, the compound fails to induce critical conformational changes in the receptor necessary for agonist activity. ..
  24. Imada K, Sato T, Hashizume K, Tanimoto A, Sasaguri Y, Ito A. An antiprogesterone, onapristone, enhances the gene expression of promatrix metalloproteinase 3/prostromelysin-1 in the uterine cervix of pregnant rabbit. Biol Pharm Bull. 2002;25:1223-7 pubmed
  25. Kawaguchi S, Bowolaksono A, Yoshioka S, Sakumoto R, Okuda K. Luteoprotective mechanisms of prostaglandin F2? stimulated by luteinizing hormone in the bovine corpus luteum. J Reprod Dev. 2013;59:225-30 pubmed
    ..05). The overall results suggest that LH prevents luteal cell death by stimulating luteal PGF and P4 production and supports CL function during the luteal phase in cattle. ..
  26. Le Cras T, Korfhagen T, Davidson C, Schmidt S, Fenchel M, Ikegami M, et al. Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Pathol. 2010;176:679-86 pubmed publisher
    ..These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy. ..
  27. Wardell S, Narayanan R, Weigel N, Edwards D. Partial agonist activity of the progesterone receptor antagonist RU486 mediated by an amino-terminal domain coactivator and phosphorylation of serine400. Mol Endocrinol. 2010;24:335-45 pubmed publisher
    ..These data underscore the structural flexibility of the NTD of PR, and the ability of steroid ligands together with interacting proteins to affect the conformation and activity of the NTD. ..
  28. Howes A, Chiang G, Lang E, Ho C, Powis G, Vuori K, et al. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther. 2007;6:2505-14 pubmed
    ..In addition, we propose that the use of three-dimensional tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in cancer cell lines lacking phosphatase and tensin homologue activity or expression. ..
  29. Liu Z, Auboeuf D, Wong J, Chen J, Tsai S, Tsai M, et al. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 2002;99:7940-4 pubmed
  30. Kim Y, Liu T, Koul D, Tiao N, Feroze A, Wang J, et al. Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM. Neuro Oncol. 2011;13:367-75 pubmed publisher
    ..Our findings suggest that inhibition of these pathways might increase tumor sensitivity to PX-866 and therefore represent a potential clinical therapeutic strategy. ..
  31. Treviño L, Bolt M, Grimm S, Edwards D, Mancini M, Weigel N. Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol. 2016;30:158-72 pubmed publisher
    ..Taken together, these results indicate that the 2 kinases regulate PR transcriptional activity by distinct mechanisms. ..
  32. Chegini N, Ma C, Tang X, Williams R. Effects of GnRH analogues, 'add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression. Mol Hum Reprod. 2002;8:1071-8 pubmed
  33. Mao S, Hu X, Hua B, Wang N, Liu X, Lu F. 15?-Hydroxylation of a steroid (13-ethyl-gon-4-en-3,17-dione) by Penicillium raistrickii in an ionic liquid/aqueous biphasic system. Biotechnol Lett. 2012;34:2113-7 pubmed publisher
    ..This is compared to a 30 % yield in a monophasic aqueous system. This suggests the potential industrial application of ILs-based biphasic systems for steroid biotransformation. ..
  34. Deng W, Gopal Y, Scott A, Chen G, Woodman S, Davies M. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 2012;25:248-58 pubmed publisher
    ..The results support the rationale for combined targeting of BRAF and the PI3K-AKT pathways and illustrate how target selection will be critical to such strategies. ..
  35. Bossis I, Nishimura S, Muchow M, Porter T. Pituitary expression of type I and type II glucocorticoid receptors during chicken embryonic development and their involvement in growth hormone cell differentiation. Endocrinology. 2004;145:3523-31 pubmed
  36. Peters M, Vanzulli S, Elizalde P, Charreau E, Goin M. Effects of antiprogestins RU486 and ZK98299 on the expression of cell cycle proteins of a medroxyprogesterone acetate (MPA)-induced murine mammary tumor. Oncol Rep. 2001;8:445-9 pubmed
    ..Cyclin D1, cyclin E, CDK2 and CDK4, did not change during treatment. These results suggest that p21 might play a role in early inhibitory stages of tumor growth induced by RU486 and ZK98299. ..
  37. Puri C, Katkam R, Sachdeva G, Patil V, Manjramkar D, Kholkute S. Endometrial contraception: modulation of molecular determinants of uterine receptivity. Steroids. 2000;65:783-94 pubmed
    ..However, no direct correlation was observed between in vivo expression of TGFbeta, LIF, and integrins, thereby lending support to the concept that there exists redundancy or multiple pathways which regulate implantation events. ..
  38. Yuan Y, Li W, Li L, Yang X, Gu R, Liu H, et al. Effects of tetrazanbigen on the protein expression in human hepatocellular carcinoma cell line QGY-7701. J Huazhong Univ Sci Technolog Med Sci. 2009;29:304-8 pubmed publisher
    ..These up-regulated or down-regulated proteins are mostly related to lipid metabolism. The TNBG antitumor mechanism is probably to influence tumor lipid metabolism, resulting in accumulation of LDs in tumor cells. ..
  39. Sereda M, Meyer zu Horste G, Suter U, Uzma N, Nave K. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med. 2003;9:1533-7 pubmed
    ..Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A...
  40. Pereira R, Marques C, Baptista M, Vasques M, Horta A. Embryos and culture cells: a model for studying the effect of progesterone. Anim Reprod Sci. 2009;111:31-40 pubmed publisher
    ..Also we can not confirm a direct association between high P4 concentrations and embryo survival during early stages, although P4 may influence early embryo development through different mechanisms mediated by the type of cells present. ..
  41. De Jonghe P, Timmerman V. Anti-steroid takes aim at neuropathy. Nat Med. 2003;9:1457-8 pubmed
  42. Keysar S, Astling D, Anderson R, Vogler B, Bowles D, Morton J, et al. A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol. 2013;7:776-90 pubmed publisher
    ..This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine. ..
  43. Schlaepfer I, Hitz C, Gijón M, Bergman B, Eckel R, Jacobsen B. Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel. Mol Cell Endocrinol. 2012;363:111-21 pubmed publisher
    ..Our studies suggest the metabolic adaptations produced by progestin provide novel metabolic targets for future combinatorial therapies for progestin-responsive breast cancers...
  44. Koper J, Molijn G, Van Uffelen C, Stigter E, Lamberts S. Antiprogestins and iatrogenic glucocorticoid resistance. Life Sci. 1997;60:617-24 pubmed
    ..This may make them more suitable than RU 38486 for application in long-term antiprogestin treatment. ..
  45. Gaytan F, Bellido C, Morales C, Sanchez Criado J. Both prolactin and progesterone in proestrus are necessary for the induction of apoptosis in the regressing corpus luteum of the rat. Biol Reprod. 1998;59:1200-6 pubmed
  46. Han X, Zhang Y, Wang K. Synthesis of diindeno-fused 4H-cyclopenta[def]phenanthren-4-ones and related compounds via benzannulated enediynyl propargylic alcohols. J Org Chem. 2005;70:2406-8 pubmed
    ..Hydrolysis of 13 and 14 furnished 4H-cyclopenta[def]phenanthren-4-ones 16 and 17, respectively. Air oxidation of an alkaline solution of dichloride 11 produced diketone 18. ..
  47. Pellissier H, Michellys P, Santelli M. Conjugate hydrocyanation of 17-acetyl-11-carbomethoxygona-1,3,5(10),13(17)-tetraenes. Steroids. 2007;72:297-304 pubmed
    ..The characteristic (1)H and (13)C NMR spectroscopic features of the synthesized steroids are reported. ..
  48. Seier J, Chwalisz K, Louw J, van der Horst G, De Kock M, du Toit D, et al. Endometrial function in vervet monkeys (Cercopithecus aethiops): morphology, beta3 integrin and insulin-like growth factor binding protein-1 expression during the menstrual cycle and pregnancy in the normal and disrupted endometrium. J Med Primatol. 2002;31:330-9 pubmed
    ..To our knowledge, this is the first time that these endometrial proteins have been investigated in vervet monkeys. This study should therefore contribute to improving our understanding of the reproductive function of this species. ..
  49. Ihle N, Lemos R, Wipf P, Yacoub A, Mitchell C, Siwak D, et al. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res. 2009;69:143-50 pubmed publisher
  50. Szabo M, Kilen S, Saberi S, Ringstrom S, Schwartz N. Antiprogestins suppress basal and activin-stimulated follicle-stimulating hormone secretion in an estrogen-dependent manner. Endocrinology. 1998;139:2223-8 pubmed
  51. Pooley C, Edwards J, Goldman M, Wang M, Marschke K, Crombie D, et al. Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore. J Med Chem. 1998;41:3461-6 pubmed
    ..This is the first disclosure of orally active nonsteroidal antiprogestins. ..
  52. Krusche C, Herrler A, Classen Linke I, Beier H. The progesterone antagonist onapristone retards the advanced endometrial transformation after gonadotropin stimulation in rabbits. Steroids. 2000;65:773-82 pubmed
    ..Therefore, postovulatory administration of a PA might be a possible strategy to modulate the advanced endometrial development in IVF-cycles. ..
  53. Alban P, Hurd C, Dinda S, Khattree N, Moudgil V. Differential regulation of retinoblastoma protein by hormonal and antihormonal agents in T47D breast cancer cells. J Steroid Biochem Mol Biol. 2001;77:135-41 pubmed
    ..Furthermore, R5020 effects on pRb phosphorylation appear PR-mediated as no cross-antagonism of pRb phosphorylation was observed: the R5020 effects were blocked by RU486 and ZK98299, but not by the pure ER antagonist, ICI 182, 780 (ICI). ..