Nemtabrutinib

Nemtabrutinib

Clinical data
Other names	MK-1026; ARQ 531
Legal status
Legal status	Investigational
Identifiers
IUPAC name (2-chloro-4-phenoxyphenyl)-(4-{[(3R,6S)-6-(hydroxymethyl)oxan-3-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
CAS Number	2095393-15-8
PubChem CID	129045720
UNII	JTZ51LIXN4
Chemical and physical data
Formula	C25H23ClN4O4
Molar mass	478.93 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(c1ccc(Oc2ccccc2)cc1Cl)c1c[nH]c2ncnc(N[C@@H]3CC[C@@H](CO)OC3)c12
InChI InChI=1S/C25H23ClN4O4/c26-21-10-17(34-16-4-2-1-3-5-16)8-9-19(21)23(32)20-11-27-24-22(20)25(29-14-28-24)30-15-6-7-18(12-31)33-13-15/h1-5,8-11,14-15,18,31H,6-7,12-13H2,(H2,27,28,29,30)/t15-,18+/m1/s1 Key:JSFCZQSJQXFJDS-QAPCUYQASA-N

Nemtabrutinib (MK-1026, formerly ARQ 531) is a small molecule drug is a Bruton's tyrosine kinase (BTK) inhibitor; unlike first generation BTK inhibitors it does not bind covalently, and inhibits the ATP binding site of BTK, and was designed to inhibit Src family kinases and kinases related to ERK signalling, along with BTK. ^[1]

Merck paid $2.7 billion to acquire the company ArQule and the drug, which at the time had just completed a Phase I clinical trial as a treatment for B-cell cancers. ^[2] As of December 2024 Merck had started Phase III trials in chronic lymphocytic leukaemia and other blood cancers, and had finished a Phase I trial for kidney disease. ^{[3] [4]}

References

1. Shirley, M (January 2022). "Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features". Targeted Oncology. 17 (1): 69–84. doi:10.1007/s11523-021-00857-8. PMC   8783859 . PMID   34905129.
2. Lisa m. Jarvis (16 December 2019). "Merck will pay $2.7 billion for ArQule" . C&EN Global Enterprise. 97 (48): 13. doi:10.1021/cen-09748-buscon4. ISSN   2474-7408. S2CID   212811804.
3. Hays, Priya (14 June 2025). "Beyond BCL2 (B cell lymphoma) and BTK (Bruton tyrosine kinase) inhibitors: novel agents and resistance mechanisms for chronic lymphocytic leukemia". Discover Oncology. 16 (1) 1100. doi:10.1007/s12672-025-02947-9. PMC   12167177 . PMID   40515863.
4. "Nemtabrutinib - Merck - AdisInsight". adisinsight.springer.com. Retrieved 13 July 2025.

Further reading

• Sevindik, Ömür Gökmen; Chen, Chang; Yang, Jing; Farooqui, Mohammed Z.H.; Paszkiewicz-Kozik, Ewa (1 June 2023). "BELLWAVE-008: A phase 3 study of the efficacy and safety of nemtabrutinib in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without TP53 aberrations". Journal of Clinical Oncology. 41 (16_suppl) TPS7594. doi:10.1200/JCO.2023.41.16_suppl.TPS7594. S2CID   259080098.
• Woyach, J.; Flinn, I. W.; Awan, F. T.; Eradat, H.; Brander, D.; Tees, M.; Parikh, S. A.; Phillips, T.; Wang, W.; Reddy, N. M.; Farooqui, M. Z.; Byrd, J. C.; Stephens, D. M. (23 June 2022). "P682: Nemtabrutinib (Mk-1026), A Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase for B-Cell Malignancies: Efficacy and Safety of the Phase 2 Dose-Expansion Bellwave-001 Study". HemaSphere. 6: 578–579. doi: 10.1097/01.HS9.0000845612.25766.0c . S2CID   250001988.
• Reiff, Sean D.; Mantel, Rose; Smith, Lisa L.; Greene, J.T.; Muhowski, Elizabeth M.; Fabian, Catherine A.; Goettl, Virginia M.; Tran, Minh; Harrington, Bonnie K.; Rogers, Kerry A.; Awan, Farrukh T.; Maddocks, Kami; Andritsos, Leslie; Lehman, Amy M.; Sampath, Deepa; Lapalombella, Rosa; Eathiraj, Sudharshan; Abbadessa, Giovanni; Schwartz, Brian; Johnson, Amy J.; Byrd, John C.; Woyach, Jennifer A. (1 October 2018). "The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation". Cancer Discovery. 8 (10): 1300–1315. doi: 10.1158/2159-8290.CD-17-1409 . PMC   6261467 . PMID   30093506.
• Woyach, Jennifer A.; Flinn, Ian W.; Awan, Farrukh T.; Eradat, Herbert; Brander, Danielle; Tees, Michael; Parikh, Sameer A.; Phillips, Tycel J.; Ghori, Razi; Reddy, Nishitha M.; Farooqui, Mohammed Z.H.; Byrd, John C.; Stephens, Deborah M. (15 November 2022). "Efficacy and Safety of Nemtabrutinib, a Wild-Type and C481S-Mutated Bruton Tyrosine Kinase Inhibitor for B-Cell Malignancies: Updated Analysis of the Open-Label Phase 1/2 Dose-Expansion Bellwave-001 Study". Blood. 140 (Supplement 1): 7004–7006. doi: 10.1182/blood-2022-163596 . S2CID   256785160.
• Woyach, Jennifer A.; Stephens, Deborah M.; Flinn, Ian W.; Bhat, Seema A.; Savage, Ronald E.; Chai, Feng; Eathiraj, Sudharshan; Reiff, Sean D.; Muhowski, Elizabeth M.; Granlund, Lindsey; Szuszkiewicz, Lyndsey; Wang, Wayne; Schwartz, Brian; Ghori, Razi; Farooqui, Mohammed Z. H.; Byrd, John C. (6 November 2023). "First in Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma". Cancer Discovery. 14 (1): 66–75. doi:10.1158/2159-8290.CD-23-0670. ISSN   2159-8290. PMID   37930156. S2CID   265032444.