News on Sacyl Pharmaceuticals …

Biology

1.     Buck, J., M.L. Sinclair, L. Schapal, M.J. Cann, and L.R. Levin, Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci U S A, 1999. 96(1): p. 79-84. https://pubmed.ncbi.nlm.nih.gov/9874775/

Details the biochemical and molecular identification of soluble adenylyl cyclase (sAC)

2.     Chen, Y., M.J. Cann, T.N. Litvin, V. Iourgenko, M.L. Sinclair, L.R. Levin, and J. Buck, Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science, 2000. 289(5479): p. 625-8. https://pubmed.ncbi.nlm.nih.gov/10915626/

Identifies bicarbonate as the unique regulator of soluble adenylyl cyclase (sAC)

3.     Esposito, G., B.S. Jaiswal, F. Xie, M.A. Krajnc-Franken, T.J. Robben, A.M. Strik, C. Kuil, R.L. Philipsen, M. van Duin, M. Conti, and J.A. Gossen, Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect. Proc Natl Acad Sci U S A, 2004. 101(9): p. 2993-8. https://pubmed.ncbi.nlm.nih.gov/14976244/

Genetic validation of sAC as essential for male fertility in mice.

4.     Hess, K.C., B.H. Jones, B. Marquez, Y. Chen, T.S. Ord, M. Kamenetsky, . . . S.B. Moss, The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization. Dev Cell, 2005. 9(2): p. 249-59. https://pubmed.ncbi.nlm.nih.gov/16054031/

Pharmacologic and genetic validation of sAC as essential for male fertility in mice.

5.     Akbari, A., G.B. Pipitone, Z. Anvar, M. Jaafarinia, M. Ferrari, P. Carrera, and M. Totonchi, ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria. Hum Reprod, 2019. 34(6): p. 1155-1164. https://pubmed.ncbi.nlm.nih.gov/31119281/

Genetic validation of sAC as essential for male fertility in humans.

6.     Balbach, M., L. Ghanem, T. Rossetti, N. Kaur, C. Ritagliati, J. Ferreira, . . . L.R. Levin, Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization. Mol Hum Reprod, 2021. 27(9). https://pubmed.ncbi.nlm.nih.gov/34463764/

In vitro demonstration that sAC inhibitors block human and mouse sperm motility and capacitation.

7.     Balbach, M., T. Rossetti, J. Ferreira, L. Ghanem, C. Ritagliati, R. Myers, P.T. Meinke, J. Buck, and L.R. Levin, On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications. 2023 Feb 14;14(1):637. doi: 10.1038/s41467-023-36119-6  https://pubmed.ncbi.nlm.nih.gov/36788210/

Preclinical in vivo validation that on-demand contraception works in males

Chemistry

1.     Kleinboelting, S., A. Diaz, S. Moniot, J. van den Heuvel, M. Weyand, L.R. Levin, J. Buck, and C. Steegborn, Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate. Proc Natl Acad Sci U S A, 2014. 111(10): p. 3727-32. https://pubmed.ncbi.nlm.nih.gov/24567411/

Details the molecular mechanism for bicarbonate regulation of sAC

2.     Ramos-Espiritu, L., S. Kleinboelting, F.A. Navarrete, A. Alvau, P.E. Visconti, F. Valsecchi, . . . J. Buck, Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nat Chem Biol, 2016. 12(10): p. 838-44. https://pubmed.ncbi.nlm.nih.gov/27547922/

Identification of a lead compound for sAC inhibitors

3.     Fushimi, M., H. Buck, M. Balbach, A. Gorovyy, J. Ferreira, T. Rossetti, . . . P.T. Meinke, Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10). ACS Med Chem Lett, 2021. 12(8): p. 1283-1287. https://pubmed.ncbi.nlm.nih.gov/34413957/

Design, synthesis, and demonstration of medicinal chemistry approach for improving sAC inhibitors.

4.     Miller, M., T. Rossetti, J. Ferreira, L. Ghanem, M. Balbach, N. Kaur, . . . P.T. Meinke, Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates. J Med Chem, 2022. 65(22): p. 15208-15226. https://pubmed.ncbi.nlm.nih.gov/36346696/

Design, synthesis, and characterization of an improved sAC inhibitor identifying efficacy defining features for an on-demand male contraceptive.

5.     Rossetti, T., J. Ferreira, L. Ghanem, H. Buck, C. Steegborn, R.W. Myers, P.T. Meinke, L.R. Levin, and J. Buck, Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential. Front Physiol, 2022. 13: p. 1013845. https://pubmed.ncbi.nlm.nih.gov/36246105/

Detailed description of assays used for testing efficacy defining features of a sAC inhibitor on demand male contraceptive.

Reviews/Perspectives

1.     Balbach, M., M. Fushimi, D.J. Huggins, C. Steegborn, P.T. Meinke, L.R. Levin, and J. Buck, Optimization of lead compounds into on-demand, nonhormonal contraceptives: leveraging a public-private drug discovery institute collaboration. Biol Reprod, 2020. 103(2): p. 176-182. https://pubmed.ncbi.nlm.nih.gov/32307523/

Introduction of on-demand male contraception principle and description of the Therapeutics Discovery Institute for applying Pharma quality medicinal chemistry to academic centers.

2.   Wiggins, S., Steegborn, C., Levin, L.R., Buck, J. Pharmacological modulation of the CO2/HCO3-/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase. Pharmacol Ther, 2018. 190: p. 173-186. doi:10.1016/j.pharmthera.2018.05.008. https://pubmed.ncbi.nlm.nih.gov/29807057/

Summary of sAC inhibitor pharmacology

3.   Ferreira, J., L.R. Levin, and J. Buck, Strategies to safely target widely expressed soluble adenylyl cyclase for contraception. Front Pharmacol, 2022. 13: p. 953903. https://pubmed.ncbi.nlm.nih.gov/36091839/

Description of on-demand male contraception approach

4. Johnston, D.S., Kopf, G.S., The urgent need for innovation in contraception. Biol Reprod, 2023. 108(4): p. 519-521. https://pubmed.ncbi.nlm.nih.gov/36780138/

Summary of the state of contraception research as of 2023.

5. Anderson, D.J., Johnston, D.S., A brief history and future prospects of contraception. Science, 2023. 380(6641): p. 154-158. https://pubmed.ncbi.nlm.nih.gov/37053322/

Summary of the state of contraception research as of 2023.

6. Meinke, P.T., Transforming Academic Drug Discovery. Chembiochem, 2022. 23(8): e202100671. https://pubmed.ncbi.nlm.nih.gov/35181980/

Description of the Therapeutics Discovery Institute for applying Pharma quality medicinal chemistry to academic centers.

7. Nickels, L., Yan, W., Nonhormonal Male Contraceptive Development-Strategies for Progress. Pharmacol Rev. 76(1):37-48. https://pubmed.ncbi.nlm.nih.gov/38101934/