Alnodesertib

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Alnodesertib

CAS 2267316-76-5

MF C18H24N6O2S MW388.49

4-[4-[(cyclopropyl-methyl-oxo-λ⁶-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine

4-[4-[(cyclopropyl-methyl-oxo-lambda6-sulfanylidene)amino]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-amine

(S)-({2-(2-aminopyridin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}imino)(cyclopropyl)(methyl)-λ6
-sulfanone
serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085

Alnodesertib (formerly known as ART0380) is an investigational, orally administered drug designed to treat various types of cancer. It is a selective inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein), a key kinase involved in DNA repair and cell cycle progression.

Mechanism of Action

Alnodesertib works by disrupting the DNA Damage Response (DDR):

Targets ATR Kinase: It selectively inhibits ATR, which cancer cells rely on to fix DNA damage caused by rapid replication.
Blocks Signaling: By blocking the phosphorylation of CHK1, it prevents the activation of DNA damage checkpoints.
Induces Apoptosis: Inhibiting these repair pathways prevents cancer cells from surviving replication stress, ultimately leading to cell death (apoptosis).

Clinical Status and Indications

As of early 2026, alnodesertib is undergoing several clinical trials:

Metastatic Colorectal Cancer (mCRC): The FDA granted Fast Track designation in September 2025 for alnodesertib in combination with irinotecan for adult patients with ATM-negative mCRC in the third-line setting.
Ovarian Cancer: In March 2026, Artios Pharma reported that a Phase 2a study reached its primary endpoint, showing that adding a low dose of alnodesertib to gemcitabine improved progression-free survival in patients with platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
Other Solid Tumours: It is being evaluated in the ongoing STELLA Phase 1/2a study for its potential across multiple solid tumour types characterized by high replication stress.

Key Facts

Feature	Details
Developer	Artios Pharma Limited
Drug Class	ATR Kinase Inhibitor
Administration	Oral
Current Phase	Phase 2 clinical trials
FDA Status	Fast Track Designation (for ATM-negative mCRC)

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019014618&_cid=P11-MN9PQ8-66581-1

EXAMPLES 39a and 39b

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

and

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4- yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

[0648] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH(0.1% DEA) = 70:30; Flow rate: 80 g / min; 20 min; Column temperature: 35 °C; Back pressure: 100 bar; Column: Gilson-281, AY 20 x 250mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6mg, 25% yield, >99% ee) as a white solid and 39b (7.1mg, 27% yield, >99% ee) as a white solid.

[0649] 39a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or (S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD3OD) δ 8.03 – 7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J =5.5, 1.4 Hz, 1H), 5.97 (s, 1H), 4.48 (d, J = 4.6 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 4.02 (dt, J = 11.3, 3.6 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.75 (dt, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.56 (m, 4H), 3.25 (tdJ, = 12.8, 3.8 Hz, 1H), 3.01 (td, J = 7.9, 4.0 Hz, 1H), 1.42 (dd, J = 10.2, 5.4 Hz, 1H), 1.31 (dt, J = 11.1, 6.2 Hz, 4H), 1.20 (dt,J = 11.3, 5.7 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388, found: 389 [M+H]⁺; R_t = 11.35 min.

[0650] 39b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or (S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 7.97 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dt, J = 5.5, 1.3 Hz, 1H), 5.97 (s, 1H), 4.50 (s, 1H), 4.08 (d, J = 12.7 Hz, 1H), 4.02 (dd, J = 11.4, 3.7 Hz, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.75 (dt, J = 11.4, 3.0 Hz, 1H), 3.66 – 3.55 (m, 4H), 3.25 (tdJ, = 12.9, 3.9 Hz, 1H), 3.05 – 2.97 (m, 1H), 1.41 (dt, J = 10.6, 5.2 Hz, 1H), 1.31 (dd, J = 11.8, 5.8 Hz, 4H), 1.20 (dt, J = 11.1, 5.6 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388, found: 389 [M+H]⁺; R_t = 15.22 min.