Nuvisertib

Nuvisertib (TP-3654) is an orally active second-generation pan-PIM kinase inhibitor with K_i values of 5 nM, 239 nM, and 42 nM against PIM-1, PIM-2, and PIM-3, respectively. Nuvisertib inhibits JAK-independent inflammatory and survival signaling pathways, reduces the production of proinflammatory cytokines, restores apoptotic sensitivity, inhibits mTORC1, MYC, and TGF-β signaling pathways, and decreases the expression of fibrosis markers. Nuvisertib selectively impairs the transport function of ABCG2, resensitizes multidrug-resistant cancer cells to cytotoxic drugs, and overcomes JAK2 inhibitor resistance. Nuvisertib can be used in research related to myelofibrosis, renal cell carcinoma, multidrug-resistant cancer, advanced solid tumors, urothelial carcinoma, and prostate adenocarcinoma^{[1][2][3][4][5][6][7][8]}. In Vitro:Nuvisertib (TP-3654) synergizes with Dordaviprone (HY-15615A) to reduce renal cell carcinoma (RCC) cell viability more potently than either agent alone^[4].
Nuvisertib (2.55-34.33 μM; 72 h) is equally cytotoxic to ABCB1-overexpressing KB-V-1, NCI-ADR-RES, MDR19-HEK293 cells; ABCG2-overexpressing S1-M1-80, H460-MX20, R482-HEK293 cells; and their respective drug-sensitive parental cells, with IC₅₀ values ranging from 2.55 to 34.33 μM^[6].
Nuvisertib (100-500 nM; 72 h) selectively resensitizes ABCG2-overexpressing S1-M1-80, H460-MX20, and R482-HEK293 cells to ABCG2 substrate drugs Topotecan (HY-13768), SN-38 (HY-13704), and Mitoxantrone (HY-13502) in a concentration-dependent manner, with fold-reversal values ranging from 1.2 to 31.9^[6].
Nuvisertib (0-1 μM) selectively inhibits ABCG2-mediated drug efflux in R482-HEK293, S1-M1-80, and H460-MX20 cells with IC₅₀ values of 140 nM, 240 nM, and 200 nM, respectively, and does not affect ABCB1-mediated drug efflux^[6].
Nuvisertib (0.1-0.5 μM; 72 h) does not affect ABCG2 protein expression in ABCG2-overexpressing S1-M1-80 or H460-MX20 cancer cells when incubated at concentrations from 0.1 to 0.5 μM for 72 h^[6].
Nuvisertib binds to the substrate-binding pocket of human ABCG2 (PDB: 6VXH) with a binding energy of -58.23 kcal/mol, forming hydrophobic interactions and one hydrogen bond with specific amino acid residues^[6].
Nuvisertib (0.03-3 μM; 12 h) dose-dependently reduces phospho-BAD^S112 levels in UM-UC-3 bladder cancer cells without altering phospho-4EBP1^Th37/46 levels^[7].
Nuvisertib (0.01-100 μM; 6 or 10 days) inhibits colony formation in T24 and UM-UC-3 bladder cancer cells, with average EC₅₀ values of 1.1 μM and 2.2 μM, respectively^[7].
Nuvisertib significantly inhibits colony growth of human MPN/MF CD34⁺ hematopoietic progenitor cells^[8].
Nuvisertib (0.5 μM; 48 h) enhances Topotecan-induced apoptosis in ABCG2-overexpressing S1-M1-80 colon cancer cells, increasing total apoptosis from approximately 4% to 23%, without inducing apoptosis on its own^[6].
Nuvisertib (0.25-1.0 μM) potently reduces proliferation and induces apoptosis in JAK2^V617F- or MPL^W515L-expressing hematopoietic cells (including Ruxolitinib (HY-50856)-resistant cells), while having only modest effects on wild-type JAK2-expressing Ba/F3-EpoR cells^[8].
Nuvisertib (10 μM starting concentration with three-fold serial dilutions; up to 120 minutes) potently inhibits purified PIM-1, PIM-2, and PIM-3 kinases with K_i values of 5 nM, 239 nM, and 42 nM, respectively, and exhibits at least 10-fold selectivity for PIM-1 over other tested kinases^[7].
Nuvisertib (30 μM starting concentration with three-fold serial dilutions) does not inhibit hERG potassium channels in CHO cells stably expressing hERG, with an IC₅₀ greater than 30 μM^[7].
Nuvisertib (0.1 nM‑100 μM) potently inhibits PIM-1-mediated BAD phosphorylation at serine 112 in transfected HEK-293 cells, with an average EC₅₀ of 67 nM^[7]. In Vivo:Nuvisertib (150 mg/kg; p.o.; once daily; 6 weeks) (TP-3654) reduces leukocytosis, splenomegaly, and bone marrow fibrosis in Jak2^V617F-induced myelofibrosis in C57BL/6 mice^[5].
Nuvisertib (150 mg/kg; p.o.; once daily; 12 weeks) preferentially inhibits Jak2^V617F mutant hematopoietic progenitors, reducing leukocytosis and thrombocytosis in chimeric C57BL/6 mice with myelofibrosis^[5].
Nuvisertib (150 mg/kg; p.o.; once daily; 3 weeks) reduces leukocytosis, splenomegaly, and bone marrow fibrosis, and improves survival in MPL^W515L-induced myelofibrosis in BALB/c mice^[5].
Nuvisertib (25 mg/kg; i.p.; 5 days on, 2 days off; 3 weeks) inhibits PIM-1-driven prostate adenocarcinoma xenograft growth in female Nu/Nu mice^[7].
Nuvisertib (25 mg/kg; i.p.; 5 days on, 2 days off; 3 weeks) inhibits PIM-2-driven fibrosarcoma xenograft growth in female Nu/Nu mice^[7].
Nuvisertib (200 mg/kg; p.o.; 5 days on, 2 days off; 3 weeks) inhibits bladder carcinoma xenograft growth in female Nu/Nu mice^[7].
Nuvisertib (200 mg/kg; p.o.; 5 days on, 2 days off; 3 weeks) inhibits prostate adenocarcinoma xenograft growth in male Nu/Nu mice^[7].