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Gartisertib (M4344; VX-803; ATR inhibitor 2) is a novel, ATP-competitive and orally bioactive ATR (ataxia telangiectasia and Rad3 related kinase) inhibitor with anticancer activity. It inhibits ATR with Ki <150 pM.
Physicochemical Properties
| Molecular Formula | C25H29F2N9O3 |
| Molecular Weight | 541.5531 |
| Exact Mass | 541.236 |
| Elemental Analysis | C, 55.45; H, 5.40; F, 7.02; N, 23.28; O, 8.86 |
| CAS # | 1613191-99-3 |
| PubChem CID | 86720912 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 0.1 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 39 |
| Complexity | 885 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC1C=NC=C(C=1N1CCC(C(N2CCN(CC2)C2COC2)=O)CC1)NC(C1C(N)=NN2C=C(C=NC2=1)F)=O |
| InChi Key | QAYHKBLKSXWOEO-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C25H29F2N9O3/c26-16-9-30-23-20(22(28)32-36(23)12-16)24(37)31-19-11-29-10-18(27)21(19)34-3-1-15(2-4-34)25(38)35-7-5-33(6-8-35)17-13-39-14-17/h9-12,15,17H,1-8,13-14H2,(H2,28,32)(H,31,37) |
| Chemical Name | 2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(oxetan-3-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide |
| Synonyms | ATR inhibitor 2; M4344; VX-803; M-4344; VX803; M 4344; VX 803; Gartisertib; gartisertib; 1613191-99-3; Gartisertib [INN]; M4344; 7OM98IUD1O; Gartisertibum |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | ATR (Ki = 150 pM) ; ATR (ataxia telangiectasia and Rad3-related protein kinase) [3] |
| ln Vitro | Gartisertib is a member of the class of pyrazolopyrimidines that is pyrazolo[1,5-a]pyrimidine substituted by amino, N-[5-fluoro-4-(4-{[4-(oxetan-3-yl)piperazin-1-yl]carbonyl}piperidin-1-yl)pyridin-3-yl]aminoacyl, and fluoro groups at positions 2, 3 and 6, respectively. It is an inhibitor of ataxia telangiectasia and Rad3 related (ATR) kinase that exhibits antineoplastic activity. It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor and an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor. It is a pyrazolopyrimidine, an organofluorine compound, an aromatic amine, a secondary carboxamide, a member of pyridines, a piperidinecarboxamide, a member of oxetanes, a N-acylpiperazine and a primary amino compound. |
| ln Vivo |
Gartisertib showed alternative lengthening of telomeres (ALT) and tumor arrest-to-regression in tumor models in single-agent efficacy studies. Triple-negative breast cancer xenograft models show tumor regression when combined with PARP inhibitors [1].
- In HBCx-9 patient-derived xenograft (PDX) models, gartisertib was administered as monotherapy or in combination with PARP inhibitors (rucaparib or talazoparib). Monotherapy with gartisertib showed little or no anti-tumour activity across various dosing regimens, including once daily (1–3 mg/kg for 28–35 days), once weekly (10–20 mg/kg for 4–6 weeks), twice weekly (5–20 mg/kg for 4–6 weeks), and three times weekly (20 mg/kg for 6 weeks). However, when combined with rucaparib or talazoparib, synergistic anti-tumour efficacy was observed, leading to tumour regression or growth inhibition that was greater than with either agent alone. [3] - In a panel of nine triple-negative breast cancer (TNBC) PDXs with diverse genetic backgrounds (BRCA-mutant, BRCA-wild type HRD positive, and HRD negative), gartisertib (10 or 20 mg/kg twice weekly for 4 cycles) was evaluated in combination with talazoparib (0.3 mg/kg daily for 28 days). The combination produced heterogeneous responses: in BRCA-mutant PDXs, talazoparib alone was highly effective and addition of gartisertib provided minimal added benefit; in HRD-negative PDXs, the combination was most effective as talazoparib alone did not stabilise tumour growth; in BRCA-wild type HRD-positive models, the combination showed greater TGI than talazoparib alone. [3] - The effects of gartisertib in the model included inhibition of single-strand break (SSB) repair (pathway 2), inhibition of double-strand break (DSB) repair (pathway 4), and override of ATR-dependent cell-cycle checkpoints (leading to delayed cell death). These mechanisms contributed to the synergistic activity observed with PARP inhibition. [3] |
| Enzyme Assay | M4344 was determined to be an adenosine triphosphate (ATP)-competitive, highly potent, and tight-binding inhibitor of ATR with a Ki of < 150 pM. Minimal inhibitory activity was observed against a large panel of unrelated protein kinases, with 308 of 312 kinases tested having a measured Ki corresponding to more than 100-fold selectivity. M4344 potently inhibits ATR-driven phosphorylated checkpoint kinase-1 (P-Chk1) phosphorylation with an IC50 of 8 nM. Profiling on a selected set of cancer cell lines showed synergy with several types of DNA damaging chemotherapeutics as well as PARP1/2 and CHK1 inhibitors. [1] |
| Animal Protocol |
In monotherapy efficacy studies M4344 showed tumor stasis to regression in tumor models with alternative lengthening of telomeres (ALT). In combination with PARP inhibitors, tumor regression could be observed in triple-negative breast cancer xenograft models. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing.[1]
- In study 1 (HBCx-9 PDX), gartisertib was administered orally at 3 mg/kg once daily for 35 days, or in an intermittent schedule of 1 week on/1 week off (3 mg/kg) for a total of 5 weeks (i.e., 3 cycles of 1 week on/1 week off plus a final 1 week on), in combination with rucaparib (50 or 100 mg/kg once or twice daily for 35 days). [3] - In study 2 (HBCx-9 PDX), gartisertib was given orally at doses of 10 or 20 mg/kg once weekly for 4 weeks, 5 or 10 mg/kg twice weekly for 4 weeks, or 1 or 3 mg/kg once daily for 28 days, in combination with rucaparib (50 mg/kg daily). [3] - In study 3 (HBCx-9 PDX), gartisertib was administered orally at 10 or 20 mg/kg once weekly for 4 weeks, 5 or 10 mg/kg twice weekly for 4 weeks, 1 or 3 mg/kg once daily for 28 days, or 3 mg/kg once daily for 7 days, in combination with talazoparib (0.15 mg/kg twice daily for 28 days). [3] - In study 4 (HBCx-9 PDX), gartisertib was dosed orally at 20 mg/kg once weekly for 6 weeks, 20 mg/kg twice weekly for 6 weeks (with dose reduction to 10 mg/kg from day 13), or 20 mg/kg three times weekly for 6 weeks, in combination with talazoparib (0.15 mg/kg twice daily for 6 or 8 weeks). [3] - In the TNBC PDX panel, gartisertib was given orally at 10 mg/kg (for HBCx-17 and HBCx-1) or 20 mg/kg (for T311R) twice weekly for 4 cycles (28 days), in combination with talazoparib (0.3 mg/kg once daily for 28 days). [3] |
| References |
[1]. Abstract 369: Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy. Experimental and Molecular Therapeutics. [2]. Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy. Pharmacol Ther. 2020 Feb 26:107518. [3]. Semi-mechanistic efficacy model for PARP + ATR inhibitors-application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs. Br J Cancer . 2025 Mar;132(5):481-491. |
| Additional Infomation |
Gartisertib is an orally available inhibitor of ataxia telangiectasia and Rad3 related (ATR) kinase, with potential antineoplastic activity. Upon oral administration,gartisertib selectively inhibits ATR activity and blocks the downstream phosphorylation of the serine/threonine protein kinase CHK1. This prevents ATR-mediated signaling, which results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, and the induction of tumor cell apoptosis. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and survival; it is activated by DNA damage caused during DNA replication-associated stress.
The protein kinase ataxia telangiectasia mutated and Rad3-related ATR is one of the key mediators of the DNA damage response. ATR is recruited to regions of single-stranded DNA, which most commonly arise during replication stress (RS). RS occurs during S-phase when the cell’s DNA replication machinery encounters problems such as unresolved DNA lesions. In addition, treatment of cells with DNA-damaging agents can lead to RS as cells progress to S-phase without resolving damage incurred by such agents. Elevated levels of RS are evident in some cancer cells, even in the absence of a DNA-damaging agent resulting from expression of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways. RS in cancer cells can drive reliance on ATR for survival and, accordingly, ATR inhibitors may have benefit as monotherapy. - Gartisertib is an ATR inhibitor being investigated in combination with PARP inhibitors (rucaparib or talazoparib) for the treatment of breast cancer, particularly in tumours with homologous recombination deficiency (HRD). The combination aims to exploit synthetic lethality by concurrently inhibiting complementary DNA damage response pathways. In preclinical PDX models, the combination showed synergistic tumour growth inhibition, with the degree of synergy depending on the genetic background (e.g., BRCA mutation, HRD status). The semi-mechanistic PK-PD model described in this study incorporates key features of gartisertib's mechanism: inhibition of SSB repair (ATR-mediated pathway), inhibition of DSB repair (ATR/HR-mediated pathway), and checkpoint override, which collectively enhance DNA damage accumulation and cell death when combined with PARP inhibition. [3] |
Solubility Data
| Solubility (In Vitro) | DMSO : ~25 mg/mL (~46.16 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (3.84 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8466 mL | 9.2328 mL | 18.4655 mL | |
| 5 mM | 0.3693 mL | 1.8466 mL | 3.6931 mL | |
| 10 mM | 0.1847 mL | 0.9233 mL | 1.8466 mL |