Pharmacokinetic Optimitzation of CCG-203971: Novel Inhibitors of the Rho/MRTF/SRF Transcriptional Pathway As Potential Antifibrotic Therapeutics for Systemic Scleroderma

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2017 Mar 14

PMID 28285914

Citations 28

Authors

Kim M Hutchings

Erika M Lisabeth

Walajapet Rajeswaran

Michael W Wilson

Roderick J Sorenson

Phillip L Campbell

Jeffrey H Ruth

Asif Amin

Pei-Suen Tsou

Jeffrey R Leipprandt

Samuel R Olson

Bo Wen

Ting Zhao

Duxin Sun

Dinesh Khanna

David A Fox

Richard R Neubig

Scott D Larsen

Affiliations

Soon will be listed here.

Abstract

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.

Citing Articles

Mechanosignaling via Integrins: Pivotal Players in Liver Fibrosis Progression and Therapy.

Sharip A, Kunz J Cells. 2025; 14(4).

PMID: 39996739 PMC: 11854242. DOI: 10.3390/cells14040266.

Matrix stiffness regulates nucleus pulposus cell glycolysis by MRTF-A-dependent mechanotransduction.

Xu H, Wei K, Ni J, Deng X, Wang Y, Xiang T Bone Res. 2025; 13(1):23.

PMID: 39952914 PMC: 11828926. DOI: 10.1038/s41413-025-00402-7.

Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: implications for the involvement of pirin.

Foda B, Baker A, Joachimiak L, Mazur M, Neubig R Front Pharmacol. 2025; 16:1505000.

PMID: 39917624 PMC: 11799239. DOI: 10.3389/fphar.2025.1505000.

Pirin does not bind to p65 or regulate NFκB-dependent gene expression but does modulate cellular quercetin levels.

Meschkewitz M, Lisabeth E, Cab-Gomez A, Leipprandt J, Neubig R bioRxiv. 2024; .

PMID: 39677728 PMC: 11642861. DOI: 10.1101/2024.12.03.626411.

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

Panesso-Gomez S, Cole A, Wield A, Anyaeche V, Shah J, Jiang Q bioRxiv. 2024; .

PMID: 39605642 PMC: 11601311. DOI: 10.1101/2024.11.15.623825.

References

Johnson L, Rodansky E, Haak A, Larsen S, Neubig R, Higgins P . Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β-induced fibrogenesis in human colonic myofibroblasts. Inflamm Bowel Dis. 2013; 20(1):154-65. PMC: 4893808. DOI: 10.1097/01.MIB.0000437615.98881.31. View

Evelyn C, Wade S, Wang Q, Wu M, Iniguez-Lluhi J, Merajver S . CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol Cancer Ther. 2007; 6(8):2249-60. DOI: 10.1158/1535-7163.MCT-06-0782. View

Rydberg P, Olsen L . Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6. ACS Med Chem Lett. 2014; 3(1):69-73. PMC: 4025842. DOI: 10.1021/ml200246f. View

Yu-Wai-Man C, Spencer-Dene B, Lee R, Hutchings K, Lisabeth E, Treisman R . Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci Rep. 2017; 7(1):518. PMC: 5428058. DOI: 10.1038/s41598-017-00212-w. View

Rydberg P, Gloriam D, Zaretzki J, Breneman C, Olsen L . SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism. ACS Med Chem Lett. 2014; 1(3):96-100. PMC: 4055970. DOI: 10.1021/ml100016x. View

Olson E, Nordheim A . Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol. 2010; 11(5):353-65. PMC: 3073350. DOI: 10.1038/nrm2890. View

Tsou P, Haak A, Khanna D, Neubig R . Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription. Am J Physiol Cell Physiol. 2014; 307(1):C2-13. PMC: 4080186. DOI: 10.1152/ajpcell.00060.2014. View

Wynn T . Fibrosis under arrest. Nat Med. 2010; 16(5):523-5. PMC: 3169997. DOI: 10.1038/nm0510-523. View

Haak A, Tsou P, Amin M, Ruth J, Campbell P, Fox D . Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther. 2014; 349(3):480-6. PMC: 4019321. DOI: 10.1124/jpet.114.213520. View

10.

Leask A . Emerging targets for the treatment of scleroderma. Expert Opin Emerg Drugs. 2012; 17(2):173-9. DOI: 10.1517/14728214.2012.678833. View

11.

Sivakumar P, Ntolios P, Jenkins G, Laurent G . Into the matrix: targeting fibroblasts in pulmonary fibrosis. Curr Opin Pulm Med. 2012; 18(5):462-9. DOI: 10.1097/MCP.0b013e328356800f. View

12.

Shiwen X, Stratton R, Nikitorowicz-Buniak J, Ahmed-Abdi B, Ponticos M, Denton C . A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis. PLoS One. 2015; 10(5):e0126015. PMC: 4425676. DOI: 10.1371/journal.pone.0126015. View

13.

Stepan A, Walker D, Bauman J, Price D, Baillie T, Kalgutkar A . Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol. 2011; 24(9):1345-410. DOI: 10.1021/tx200168d. View

14.

Bell J, Haak A, Wade S, Kirchhoff P, Neubig R, Larsen S . Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents. Bioorg Med Chem Lett. 2013; 23(13):3826-32. PMC: 3707396. DOI: 10.1016/j.bmcl.2013.04.080. View

15.

Sisson T, Ajayi I, Subbotina N, Dodi A, Rodansky E, Chibucos L . Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am J Pathol. 2015; 185(4):969-86. PMC: 4380846. DOI: 10.1016/j.ajpath.2014.12.005. View

16.

Hinz B, Phan S, Thannickal V, Prunotto M, Desmouliere A, Varga J . Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012; 180(4):1340-55. PMC: 3640252. DOI: 10.1016/j.ajpath.2012.02.004. View

17.

Sandbo N, Lau A, Kach J, Ngam C, Yau D, Dulin N . Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-β. Am J Physiol Lung Cell Mol Physiol. 2011; 301(5):L656-66. PMC: 3213993. DOI: 10.1152/ajplung.00166.2011. View

18.

Evelyn C, Bell J, Ryu J, Wade S, Kocab A, Harzdorf N . Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg Med Chem Lett. 2009; 20(2):665-72. PMC: 2818594. DOI: 10.1016/j.bmcl.2009.11.056. View