19-Chloro-22-(2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl)-13,16-difluoro-3-propan-2-yl-8,11-dioxa-1,4,23,26-tetrazapentacyclo[16.6.2.02,7.012,17.021,25]hexacosa-2(7),3,5,12,14,16,18,20,22,25-decaen-24-one
[CAS# 2641216-67-1]

Identification

• Classification: Organic raw materials >> Ketone compound
• Name: 19-Chloro-22-(2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl)-13,16-difluoro-3-propan-2-yl-8,11-dioxa-1,4,23,26-tetrazapentacyclo[16.6.2.02,7.012,17.021,25]hexacosa-2(7),3,5,12,14,16,18,20,22,25-decaen-24-one
• Synonyms: MK-1084; 22-[(2S,5R)-4-Acryloyl-2,5-dimethyl-1-piperazinyl]-19-chloro-13,16-difluoro-3-isopropyl-8,11-dioxa-1,4,23,26-tetraazapentacyclo[16.6.2.0~2,7~.0~12,17~.0~21,25~]hexacosa-2,4,6,12,14,16,18,20,22,25-deca en-24-one
• Molecular Formula: C₃₂H₃₁ClF₂N₆O₄
• Molecular Weight: 637.08
• CAS Registry Number: 2641216-67-1
• SMILES: CC1CN(C(CN1C(=O)C=C)C)C2=NC(=O)N3C4=C(C=CN=C4C(C)C)OCCOC5=C(C=CC(=C5C6=C(C=C2C3=N6)Cl)F)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 788.9±70.0 °C 760 mmHg (Calc.)^*
• Flash point: 430.9±35.7 °C (Calc.)^*
• Index of refraction: 1.666 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P3

Discovery and Applications

19-chloro-22-(2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl)-13,16-difluoro-3-propan-2-yl-8,11-dioxa-1,4,23,26-tetrazapentacyclo[16.6.2.0^2,7.0^12,17.0^21,25]hexacosa-2(7),3,5,12,14,16,18,20,22,25-decaen-24-one is the systematic name for the investigational oncology agent commonly referred to as MK-1084 (INN: calderasib). The substance is a synthetically derived small molecule designed as a selective covalent inhibitor of the KRAS G12C mutant protein. Structurally it is a compact, polycyclic macrocyclic-like framework bearing a substituted piperazine appendage, two fluorine atoms and a single chlorine atom on the polycyclic core; these features contribute to its physicochemical profile, oral bioavailability and target engagement properties.

The discovery programme that produced MK-1084 employed structure-based design and medicinal-chemistry optimisation to create an orally bioavailable, low-dose covalent inhibitor that selectively targets the cysteine at position 12 of the KRAS G12C oncoprotein. Chemical optimisation focused on achieving potent biochemical and cellular inhibition of KRAS G12C while improving metabolic stability and tolerability. The resulting molecule engages the inactive GDP-bound state of KRAS G12C, forming a covalent bond with the mutant cysteine and thereby inhibiting downstream MAPK signalling pathways in KRAS G12C-mutant tumour cells. Preclinical characterisation demonstrated potent biochemical potency and cellular activity consistent with a targeted covalent mechanism of action.

MK-1084 advanced from discovery through preclinical evaluation into clinical development. Early human studies comprised a first-in-human phase 1 programme evaluating monotherapy dosing and combination regimens. Clinical study designs included dose-escalation cohorts to characterise safety, pharmacokinetics and pharmacodynamics, together with expansion cohorts in patients with KRAS G12C-mutant solid tumours. Results reported from the phase 1 programme indicate a tolerable safety profile and evidence of antitumour activity as a single agent in previously treated patients and substantial responses in combination with the anti-PD-1 antibody pembrolizumab in treatment-naive non-small cell lung cancer cohorts. These clinical data supported further development, including planned or ongoing randomized studies combining MK-1084 with immunotherapy.

The principal application of MK-1084 is as a targeted anticancer therapeutic for tumours harbouring the KRAS G12C mutation. In clinical practice if approved, such agents are intended to be administered orally and used either as monotherapy or in combination with other anticancer modalities. The development trajectory for MK-1084 reflects broader clinical strategies for KRAS G12C inhibition, where next-generation molecules seek improved potency, durability of response and compatibility with combination regimens to overcome adaptive resistance mechanisms observed with earlier compounds in the class.

From a practical and translational perspective, MK-1084 exemplifies modern covalent inhibitor design: selective covalent engagement of a mutant cysteine residue, optimisation for oral dosing, and integration into combination clinical regimens. Ongoing and reported clinical data emphasise both the activity and the safety considerations that guide dose selection and combination strategies. The emergence of MK-1084 as a clinical candidate contributes to the expanding therapeutic landscape for KRAS-mutant cancers and to the evolving evidence base on how best to deploy KRAS G12C inhibitors clinically.

References

Ma X, Sloman DL, Duggal R, et al. (2024) Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS^G12C Inhibitor. Journal of Medicinal Chemistry 67(13) 11024–11052. DOI: 10.1021/acs.jmedchem.4c00572

Rojas CI, Lugowska I, Juergens R, et al. (2024) Updated results from a phase I study evaluating the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC. ESMO Open 9 (suppl) 102273. DOI: 10.1016/j.esmoop.2024.102273

Miyashita H, Kato S & Hong DS (2024) KRAS G12C inhibitor combination therapies: current evidence and challenges. Frontiers in Oncology 14 1380584. DOI: 10.3389/fonc.2024.1380584