SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile

Novartis Pharma AG, Research Transplantation, WSJ-386, CH - 4002 Basel, Switzerland. Christian.Bruns@pharma.novartis.com

OBJECTIVE: The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. DESIGN: A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. RESULTS: SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. CONCLUSION: We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.

This article has been cited by other articles:

				C. E. Higham and P. J. Trainer Growth hormone excess and the development of growth hormone receptor antagonists Exp Physiol, November 1, 2008; 93(11): 1157 - 1169. [Abstract] [Full Text] [PDF]

				S. Grozinsky-Glasberg, I. Shimon, M. Korbonits, and A. B Grossman Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms Endocr. Relat. Cancer, September 1, 2008; 15(3): 701 - 720. [Abstract] [Full Text] [PDF]

				C. de Bruin, J. M. Hanson, B. P. Meij, H. S. Kooistra, A. M. Waaijers, P. Uitterlinden, S. W. J. Lamberts, and L. J. Hofland Expression and Functional Analysis of Dopamine Receptor Subtype 2 and Somatostatin Receptor Subtypes in Canine Cushing's Disease Endocrinology, September 1, 2008; 149(9): 4357 - 4366. [Abstract] [Full Text] [PDF]

				B. M. K. Biller, A. B. Grossman, P. M. Stewart, S. Melmed, X. Bertagna, J. Bertherat, M. Buchfelder, A. Colao, A. R. Hermus, L. J. Hofland, et al. Treatment of Adrenocorticotropin-Dependent Cushing's Syndrome: A Consensus Statement J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2454 - 2462. [Abstract] [Full Text] [PDF]

				A. Fusco, G. Gunz, P. Jaquet, H. Dufour, A. L. Germanetti, M. D Culler, A. Barlier, and A. Saveanu Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas Eur. J. Endocrinol., May 1, 2008; 158(5): 595 - 603. [Abstract] [Full Text] [PDF]

				R Borie, A Fabre, F Prost, J Marchal-Somme, R Lebtahi, S Marchand-Adam, M Aubier, P Soler, and B Crestani Activation of somatostatin receptors attenuates pulmonary fibrosis Thorax, March 1, 2008; 63(3): 251 - 258. [Abstract] [Full Text] [PDF]

				L. A. Nolan, H. A. Schmid, and A. Levy Octreotide and the Novel Multireceptor Ligand Somatostatin Receptor Agonist Pasireotide (SOM230) Block the Adrenalectomy-Induced Increase in Mitotic Activity in Male Rat Anterior Pituitary Endocrinology, June 1, 2007; 148(6): 2821 - 2827. [Abstract] [Full Text] [PDF]

				M. Fedele, I. De Martino, R. Pivonello, A. Ciarmiello, M. L. Del Basso De Caro, R. Visone, D. Palmieri, G. M. Pierantoni, C. Arra, H. A. Schmid, et al. SOM230, A New Somatostatin Analogue, Is Highly Effective in the Therapy of Growth Hormone/Prolactin-Secreting Pituitary Adenomas Clin. Cancer Res., May 1, 2007; 13(9): 2738 - 2744. [Abstract] [Full Text] [PDF]

				T. Scholz, G. Eisenhofer, K. Pacak, H. Dralle, and H. Lehnert Current Treatment of Malignant Pheochromocytoma J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1217 - 1225. [Abstract] [Full Text] [PDF]

				J. van der Hoek, S. W J Lamberts, and L. J Hofland Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas Eur. J. Endocrinol., April 1, 2007; 156(suppl_1): S45 - S51. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, D. Piccin, C. Vignali, F. Tagliati, M. R. Ambrosio, M. Bondanelli, V. Cimino, A. Bianchi, H. A Schmid, M. Scanarini, et al. Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion Endocr. Relat. Cancer, March 1, 2007; 14(1): 91 - 102. [Abstract] [Full Text] [PDF]

				M. Duran-Prado, C. Bucharles, B. J. Gonzalez, R. Vazquez-Martinez, A. J. Martinez-Fuentes, S. Garcia-Navarro, S. J. Rhodes, H. Vaudry, M. M. Malagon, and J. P. Castano Porcine Somatostatin Receptor 2 Displays Typical Pharmacological sst2 Features but Unique Dynamics of Homodimerization and Internalization Endocrinology, January 1, 2007; 148(1): 411 - 421. [Abstract] [Full Text] [PDF]

				C Susini and L Buscail Rationale for the use of somatostatin analogs as antitumor agents Ann. Onc., December 1, 2006; 17(12): 1733 - 1742. [Abstract] [Full Text] [PDF]

				D. L. Batista, X. Zhang, R. Gejman, P. J. Ansell, Y. Zhou, S. A. Johnson, B. Swearingen, E. T. Hedley-Whyte, C. A. Stratakis, and A. Klibanski The Effects of SOM230 on Cell Proliferation and Adrenocorticotropin Secretion in Human Corticotroph Pituitary Adenomas J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4482 - 4488. [Abstract] [Full Text] [PDF]

				E. Hubina, A. M Nanzer, M. R Hanson, E. Ciccarelli, M. Losa, D. Gaia, M. Papotti, M. R. Terreni, S. Khalaf, S. Jordan, et al. Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur. J. Endocrinol., August 1, 2006; 155(2): 371 - 379. [Abstract] [Full Text] [PDF]

				S. V. de Sa, M. L. Correa-Giannella, M. C. Machado, J. J. S de Souza, M. A. A. Pereira, R. A. Patzina, S. A. C. Siqueira, M. C. C. Machado, and D. Giannella-Neto Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas. Endocr. Relat. Cancer, March 1, 2006; 13(1): 69 - 78. [Abstract] [Full Text] [PDF]

				W. Ruan, F. Fahlbusch, D. R. Clemmons, M. E. Monaco, P. D. Walden, A. P. Silva, H. A. Schmid, and D. L. Kleinberg SOM230 Inhibits Insulin-Like Growth Factor-I Action in Mammary Gland Development by Pituitary Independent Mechanism: Mediated through Somatostatin Subtype Receptor 3? Mol. Endocrinol., February 1, 2006; 20(2): 426 - 436. [Abstract] [Full Text] [PDF]

				G A Kaltsas, D Papadogias, P Makras, and A B Grossman Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues Endocr. Relat. Cancer, December 1, 2005; 12(4): 683 - 699. [Abstract] [Full Text] [PDF]

				A P Silva, P Schoeffter, G Weckbecker, C Bruns, and H A Schmid Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats Eur. J. Endocrinol., September 1, 2005; 153(3): R7 - R10. [Abstract] [Full Text] [PDF]

				J. van der Hoek, M. Waaijers, P. M. van Koetsveld, D. Sprij-Mooij, R. A. Feelders, H. A. Schmid, P. Schoeffter, D. Hoyer, D. Cervia, J. E. Taylor, et al. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E278 - E287. [Abstract] [Full Text] [PDF]

				B. Astruc, P. Marbach, H. Bouterfa, C. Denot, M. Safari, A. Vitaliti, and M. Sheppard Long-Acting Octreotide and Prolonged-Release Lanreotide Formulations Have Different Pharmacokinetic Profiles J. Clin. Pharmacol., July 1, 2005; 45(7): 836 - 844. [Abstract] [Full Text] [PDF]

				A. P Silva, K. Bethmann, F. Raulf, and H. A Schmid Regulation of ghrelin secretion by somatostatin analogs in rats Eur. J. Endocrinol., June 1, 2005; 152(6): 887 - 894. [Abstract] [Full Text] [PDF]

				G. A. Kaltsas, P. Nomikos, G. Kontogeorgos, M. Buchfelder, and A. B. Grossman Diagnosis and Management of Pituitary Carcinomas J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3089 - 3099. [Abstract] [Full Text] [PDF]

				L. J Hofland, J. van der Hoek, R. Feelders, M. O van Aken, P. M van Koetsveld, M. Waaijers, D. Sprij-Mooij, C. Bruns, G. Weckbecker, W. W de Herder, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5 Eur. J. Endocrinol., April 1, 2005; 152(4): 645 - 654. [Abstract] [Full Text] [PDF]

				J. S. Bevan The Antitumoral Effects of Somatostatin Analog Therapy in Acromegaly J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1856 - 1863. [Abstract] [Full Text] [PDF]

				J. L. Wemeau, P. Caron, A. Beckers, V. Rohmer, J. Orgiazzi, F. Borson-Chazot, M. Nocaudie, P. Perimenis, S. Bisot-Locard, I. Bourdeix, et al. Octreotide (Long-Acting Release Formulation) Treatment in Patients with Graves' Orbitopathy: Clinical Results of a Four-Month, Randomized, Placebo-Controlled, Double-Blind Study J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 841 - 848. [Abstract] [Full Text] [PDF]

				M. Ginj, J. Chen, M. A. Walter, V. Eltschinger, J. C. Reubi, and H. R. Maecke Preclinical Evaluation of New and Highly Potent Analogues of Octreotide for Predictive Imaging and Targeted Radiotherapy Clin. Cancer Res., February 1, 2005; 11(3): 1136 - 1145. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, D. Piccin, A. Bottoni, M. R. Ambrosio, A. Margutti, R. Padovani, M. Scanarini, J. E. Taylor, M. D. Culler, L. Cavazzini, et al. Evidence for Differential Effects of Selective Somatostatin Receptor Subtype Agonists on {alpha}-Subunit and Chromogranin A Secretion and on Cell Viability in Human Nonfunctioning Pituitary Adenomas in Vitro J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5181 - 5188. [Abstract] [Full Text] [PDF]

				G. A. Kaltsas, G. M. Besser, and A. B. Grossman The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors Endocr. Rev., June 1, 2004; 25(3): 458 - 511. [Abstract] [Full Text] [PDF]

				R. D. Murray, K. Kim, S.-G. Ren, I. Lewis, G. Weckbecker, C. Bruns, and S. Melmed The Novel Somatostatin Ligand (SOM230) Regulates Human and Rat Anterior Pituitary Hormone Secretion J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3027 - 3032. [Abstract] [Full Text] [PDF]

				K. Oberg, L. Kvols, M. Caplin, G. Delle Fave, W. de Herder, G. Rindi, P. Ruszniewski, E. A. Woltering, and B. Wiedenmann Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system Ann. Onc., June 1, 2004; 15(6): 966 - 973. [Abstract] [Full Text] [PDF]

				L. J. Hofland, J. van der Hoek, P. M. van Koetsveld, W. W. de Herder, M. Waaijers, D. Sprij-Mooij, C. Bruns, G. Weckbecker, R. Feelders, A.-J. van der Lely, et al. The Novel Somatostatin Analog SOM230 Is a Potent Inhibitor of Hormone Release by Growth Hormone- and Prolactin-Secreting Pituitary Adenomas in Vitro J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1577 - 1585. [Abstract] [Full Text] [PDF]

				J. van der Hoek, W. W. de Herder, R. A. Feelders, A.-J. van der Lely, P. Uitterlinden, V. Boerlin, C. Bruns, K. W. Poon, I. Lewis, G. Weckbecker, et al. A Single-Dose Comparison of the Acute Effects between the New Somatostatin Analog SOM230 and Octreotide in Acromegalic Patients J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 638 - 645. [Abstract] [Full Text] [PDF]

				M. C. Zatelli, D. Piccin, F. Tagliati, M. R. Ambrosio, A. Margutti, R. Padovani, M. Scanarini, M. D. Culler, and E. C. degli Uberti Somatostatin Receptor Subtype 1 Selective Activation in Human Growth Hormone (GH)- and Prolactin (PRL)-Secreting Pituitary Adenomas: Effects on Cell Viability, GH, and PRL Secretion J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2797 - 2802. [Abstract] [Full Text] [PDF]

				L. J. Hofland and S. W. J. Lamberts The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance Endocr. Rev., February 1, 2003; 24(1): 28 - 47. [Abstract] [Full Text] [PDF]