TY - JOUR
T1 - MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer
AU - Engstrom, Lars D.
AU - Aranda, Ruth
AU - Waters, Laura
AU - Moya, Krystal
AU - Bowcut, Vickie
AU - Vegar, Laura
AU - Trinh, David
AU - Hebbert, Allan
AU - Smith, Christopher R.
AU - Kulyk, Svitlana
AU - Lawson, J. David
AU - He, Leo
AU - Hover, Laura D.
AU - Fernandez-Banet, Julio
AU - Hallin, Jill
AU - Vanderpool, Darin
AU - Briere, David M.
AU - Blaj, Alice
AU - Marx, Matthew A.
AU - Rodon, Jordi
AU - Offin, Michael
AU - Arbour, Kathryn C.
AU - Johnson, Melissa L.
AU - Kwiatkowski, David J.
AU - Jänne, Pasi A.
AU - Haddox, Candace L.
AU - Papadopoulos, Kyriakos P.
AU - Henry, Jason T.
AU - Leventakos, Konstantinos
AU - Christensen, James G.
AU - Shazer, Ronald
AU - Olson, Peter
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmaco-logic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study.
AB - Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmaco-logic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study.
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UR - http://www.scopus.com/inward/citedby.url?scp=85175878089&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-23-0669
DO - 10.1158/2159-8290.CD-23-0669
M3 - Article
C2 - 37552839
AN - SCOPUS:85175878089
SN - 2159-8274
VL - 13
SP - 2412
EP - 2431
JO - Cancer discovery
JF - Cancer discovery
IS - 11
ER -