Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

Michael J. Soth; Kang Le; Maria Emilia Di Francesco; Matthew M. Hamilton; Gang Liu; Jason P. Burke; Chris L. Carroll; Jeffrey J. Kovacs; Jennifer P. Bardenhagen; Christopher A. Bristow; Mario Cardozo; Barbara Czako; Elisa De Stanchina; Ningping Feng; Jill R. Garvey; Jason P. Gay; Mary K.Geck Do; Jennifer Greer; Michelle Han; Angela Harris; Zachary Herrera; Sha Huang; Virginia Giuliani; Yongying Jiang; Sarah B. Johnson; Troy A. Johnson; Zhijun Kang; Paul G. Leonard; Zhen Liu; Timothy McAfoos; Meredith Miller; Pietro Morlacchi; Robert A. Mullinax; Wylie S. Palmer; Jihai Pang; Norma Rogers; Charles M. Rudin; Hannah E. Shepard; Nakia D. Spencer; Jay Theroff; Qi Wu; Alan Xu; Ju Anne Yau; Giulio Draetta; Carlo Toniatti; Timothy P. Heffernan; Philip Jones

doi:10.1021/acs.jmedchem.0c01398

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

Michael J. Soth, Kang Le, Maria Emilia Di Francesco, Matthew M. Hamilton, Gang Liu, Jason P. Burke, Chris L. Carroll, Jeffrey J. Kovacs, Jennifer P. Bardenhagen, Christopher A. Bristow, Mario Cardozo, Barbara Czako, Elisa De Stanchina, Ningping Feng, Jill R. Garvey, Jason P. Gay, Mary K.Geck Do, Jennifer Greer, Michelle Han, Angela HarrisZachary Herrera, Sha Huang, Virginia Giuliani, Yongying Jiang, Sarah B. Johnson, Troy A. Johnson, Zhijun Kang, Paul G. Leonard, Zhen Liu, Timothy McAfoos, Meredith Miller, Pietro Morlacchi, Robert A. Mullinax, Wylie S. Palmer, Jihai Pang, Norma Rogers, Charles M. Rudin, Hannah E. Shepard, Nakia D. Spencer, Jay Theroff, Qi Wu, Alan Xu, Ju Anne Yau, Giulio Draetta, Carlo Toniatti, Timothy P. Heffernan, Philip Jones

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

48 Scopus citations

Abstract

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

Original language	English (US)
Pages (from-to)	12957-12977
Number of pages	21
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	21
DOIs	https://doi.org/10.1021/acs.jmedchem.0c01398
State	Published - Nov 12 2020

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Soth, M. J., Le, K., Di Francesco, M. E., Hamilton, M. M., Liu, G., Burke, J. P., Carroll, C. L., Kovacs, J. J., Bardenhagen, J. P., Bristow, C. A., Cardozo, M., Czako, B., De Stanchina, E., Feng, N., Garvey, J. R., Gay, J. P., Do, M. K. G., Greer, J., Han, M., ... Jones, P. (2020). Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties. Journal of Medicinal Chemistry, 63(21), 12957-12977. https://doi.org/10.1021/acs.jmedchem.0c01398

Soth, MJ, Le, K, Di Francesco, ME, Hamilton, MM, Liu, G, Burke, JP, Carroll, CL, Kovacs, JJ, Bardenhagen, JP , Bristow, CA, Cardozo, M, Czako, B, De Stanchina, E, Feng, N, Garvey, JR, Gay, JP, Do, MKG, Greer, J, Han, M, Harris, A, Herrera, Z, Huang, S, Giuliani, V , Jiang, Y, Johnson, SB, Johnson, TA, Kang, Z, Leonard, PG, Liu, Z, McAfoos, T, Miller, M, Morlacchi, P, Mullinax, RA, Palmer, WS, Pang, J, Rogers, N, Rudin, CM, Shepard, HE, Spencer, ND, Theroff, J, Wu, Q, Xu, A, Yau, JA, Draetta, G, Toniatti, C, Heffernan, TP & Jones, P 2020, 'Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties', Journal of Medicinal Chemistry, vol. 63, no. 21, pp. 12957-12977. https://doi.org/10.1021/acs.jmedchem.0c01398

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title = "Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties",

abstract = "Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.",

author = "Soth, {Michael J.} and Kang Le and {Di Francesco}, {Maria Emilia} and Hamilton, {Matthew M.} and Gang Liu and Burke, {Jason P.} and Carroll, {Chris L.} and Kovacs, {Jeffrey J.} and Bardenhagen, {Jennifer P.} and Bristow, {Christopher A.} and Mario Cardozo and Barbara Czako and {De Stanchina}, Elisa and Ningping Feng and Garvey, {Jill R.} and Gay, {Jason P.} and Do, {Mary K.Geck} and Jennifer Greer and Michelle Han and Angela Harris and Zachary Herrera and Sha Huang and Virginia Giuliani and Yongying Jiang and Johnson, {Sarah B.} and Johnson, {Troy A.} and Zhijun Kang and Leonard, {Paul G.} and Zhen Liu and Timothy McAfoos and Meredith Miller and Pietro Morlacchi and Mullinax, {Robert A.} and Palmer, {Wylie S.} and Jihai Pang and Norma Rogers and Rudin, {Charles M.} and Shepard, {Hannah E.} and Spencer, {Nakia D.} and Jay Theroff and Qi Wu and Alan Xu and Yau, {Ju Anne} and Giulio Draetta and Carlo Toniatti and Heffernan, {Timothy P.} and Philip Jones",

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month = nov,

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doi = "10.1021/acs.jmedchem.0c01398",

language = "English (US)",

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AU - Soth, Michael J.

AU - Le, Kang

AU - Di Francesco, Maria Emilia

AU - Hamilton, Matthew M.

AU - Liu, Gang

AU - Burke, Jason P.

AU - Carroll, Chris L.

AU - Kovacs, Jeffrey J.

AU - Bardenhagen, Jennifer P.

AU - Bristow, Christopher A.

AU - Cardozo, Mario

AU - Czako, Barbara

AU - De Stanchina, Elisa

AU - Feng, Ningping

AU - Garvey, Jill R.

AU - Gay, Jason P.

AU - Do, Mary K.Geck

AU - Greer, Jennifer

AU - Han, Michelle

AU - Harris, Angela

AU - Herrera, Zachary

AU - Huang, Sha

AU - Giuliani, Virginia

AU - Jiang, Yongying

AU - Johnson, Sarah B.

AU - Johnson, Troy A.

AU - Kang, Zhijun

AU - Leonard, Paul G.

AU - Liu, Zhen

AU - McAfoos, Timothy

AU - Miller, Meredith

AU - Morlacchi, Pietro

AU - Mullinax, Robert A.

AU - Palmer, Wylie S.

AU - Pang, Jihai

AU - Rogers, Norma

AU - Rudin, Charles M.

AU - Shepard, Hannah E.

AU - Spencer, Nakia D.

AU - Theroff, Jay

AU - Wu, Qi

AU - Xu, Alan

AU - Yau, Ju Anne

AU - Draetta, Giulio

AU - Toniatti, Carlo

AU - Heffernan, Timothy P.

AU - Jones, Philip

PY - 2020/11/12

Y1 - 2020/11/12

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Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

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