Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

Barbara Czako; Joseph R. Marszalek; Jason P. Burke; Pijus Mandal; Paul G. Leonard; Jason B. Cross; Faika Mseeh; Yongying Jiang; Edward Q. Chang; Erika Suzuki; Jeffrey J. Kovacs; Ningping Feng; Sonal Gera; Angela L. Harris; Zhen Liu; Robert A. Mullinax; Jihai Pang; Connor A. Parker; Nakia D. Spencer; Simon S. Yu; Qi Wu; Martin R. Tremblay; Keith Mikule; Keith Wilcoxen; Timothy P. Heffernan; Giulio F. Draetta; Philip Jones

doi:10.1021/acs.jmedchem.0c00936

Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

Barbara Czako, Joseph R. Marszalek, Jason P. Burke, Pijus Mandal, Paul G. Leonard, Jason B. Cross, Faika Mseeh, Yongying Jiang, Edward Q. Chang, Erika Suzuki, Jeffrey J. Kovacs, Ningping Feng, Sonal Gera, Angela L. Harris, Zhen Liu, Robert A. Mullinax, Jihai Pang, Connor A. Parker, Nakia D. Spencer, Simon S. YuQi Wu, Martin R. Tremblay, Keith Mikule, Keith Wilcoxen, Timothy P. Heffernan, Giulio F. Draetta, Philip Jones

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.

Original language	English (US)
Pages (from-to)	9888-9911
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00936
State	Published - Sep 10 2020

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/acs.jmedchem.0c00936

Cite this

Czako, B., Marszalek, J. R., Burke, J. P., Mandal, P., Leonard, P. G., Cross, J. B., Mseeh, F., Jiang, Y., Chang, E. Q., Suzuki, E., Kovacs, J. J., Feng, N., Gera, S., Harris, A. L., Liu, Z., Mullinax, R. A., Pang, J., Parker, C. A., Spencer, N. D., ... Jones, P. (2020). Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R. Journal of Medicinal Chemistry, 63(17), 9888-9911. https://doi.org/10.1021/acs.jmedchem.0c00936

Czako, B, Marszalek, JR, Burke, JP, Mandal, P, Leonard, PG, Cross, JB, Mseeh, F , Jiang, Y , Chang, EQ , Suzuki, E, Kovacs, JJ, Feng, N, Gera, S, Harris, AL, Liu, Z, Mullinax, RA, Pang, J, Parker, CA, Spencer, ND, Yu, SS, Wu, Q, Tremblay, MR, Mikule, K, Wilcoxen, K, Heffernan, TP, Draetta, GF & Jones, P 2020, 'Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R', Journal of Medicinal Chemistry, vol. 63, no. 17, pp. 9888-9911. https://doi.org/10.1021/acs.jmedchem.0c00936

@article{9b7458e875184f37bd958b2928f52bb8,

title = "Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R",

abstract = "Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.",

author = "Barbara Czako and Marszalek, {Joseph R.} and Burke, {Jason P.} and Pijus Mandal and Leonard, {Paul G.} and Cross, {Jason B.} and Faika Mseeh and Yongying Jiang and Chang, {Edward Q.} and Erika Suzuki and Kovacs, {Jeffrey J.} and Ningping Feng and Sonal Gera and Harris, {Angela L.} and Zhen Liu and Mullinax, {Robert A.} and Jihai Pang and Parker, {Connor A.} and Spencer, {Nakia D.} and Yu, {Simon S.} and Qi Wu and Tremblay, {Martin R.} and Keith Mikule and Keith Wilcoxen and Heffernan, {Timothy P.} and Draetta, {Giulio F.} and Philip Jones",

note = "Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = sep,

day = "10",

doi = "10.1021/acs.jmedchem.0c00936",

language = "English (US)",

volume = "63",

pages = "9888--9911",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "17",

}

TY - JOUR

T1 - Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

AU - Czako, Barbara

AU - Marszalek, Joseph R.

AU - Burke, Jason P.

AU - Mandal, Pijus

AU - Leonard, Paul G.

AU - Cross, Jason B.

AU - Mseeh, Faika

AU - Jiang, Yongying

AU - Chang, Edward Q.

AU - Suzuki, Erika

AU - Kovacs, Jeffrey J.

AU - Feng, Ningping

AU - Gera, Sonal

AU - Harris, Angela L.

AU - Liu, Zhen

AU - Mullinax, Robert A.

AU - Pang, Jihai

AU - Parker, Connor A.

AU - Spencer, Nakia D.

AU - Yu, Simon S.

AU - Wu, Qi

AU - Tremblay, Martin R.

AU - Mikule, Keith

AU - Wilcoxen, Keith

AU - Heffernan, Timothy P.

AU - Draetta, Giulio F.

AU - Jones, Philip

PY - 2020/9/10

Y1 - 2020/9/10

N2 - Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.

AB - Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.

UR - http://www.scopus.com/inward/record.url?scp=85090869420&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85090869420&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.0c00936

DO - 10.1021/acs.jmedchem.0c00936

M3 - Article

C2 - 32787110

AN - SCOPUS:85090869420

SN - 0022-2623

VL - 63

SP - 9888

EP - 9911

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this