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Chemical Structure| 2040291-27-6 Chemical Structure| 2040291-27-6

Structure of LLY-283
CAS No.: 2040291-27-6

Chemical Structure| 2040291-27-6

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LLY-283 is a potent, selective and oral protein arginine methyltransferase 5 (PRMT5) inhibitor, with an IC50 of 22 nM and a Kd of 6 nM for PRMT5:MEP50 complex, and shows antitumor activity.

Synonyms: LLY-283

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Product Citations

Product Citations

Zhou, Jujun ; Deng, Youchao ; Iyamu, Iredia D. ; Horton, John R. ; Yu, Dan ; Hajian, Taraneh , et al.

Abstract: S-Adenosyl-L-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host-pathogen interactions, one of which is Clostridioides difficile-specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds (6e and 7), we designed an adenosine analog (11a) carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-Et moiety at the sulfur atom off the ribose ring. Compound 11a (IC50 = 0.15 μM) is 10x and 5x more potent against CamA than 6e and 7, resp. The structure of the CamA-DNA-inhibitor complex revealed that 11a adopts a U-shaped conformation, with the two branches folded toward each other, and the aliphatic and aromatic rings at the two ends interacting with one another. 11a occupies the entire hydrophobic surface (apparently unique to CamA) next to the adenosine binding site. Our work presents a hybrid knowledge-based and fragment-based approach to generating CamA inhibitors that would be chem. agents to examine the mechanism(s) of action and therapeutic potentials of CamA in C. difficile infection.

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Product Details of LLY-283

CAS No. :2040291-27-6
Formula : C17H18N4O4
M.W : 342.35
SMILES Code : NC1=C2C(N([C@H]3[C@@H]([C@@H]([C@@H]([C@@H](C4=CC=CC=C4)O)O3)O)O)C=C2)=NC=N1
Synonyms :
LLY-283
MDL No. :N/A

Safety of LLY-283

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Related Pathways of LLY-283

epigenetics

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description References
Patient-derived GBM stem cells (GSCs) 1 μM 5 days Inhibition of PRMT5 activity, significant reduction of SDMA mark Nat Commun. 2021 Feb 12;12(1):979
GBMNS (GBM43) 6 µM TMZ, 3 µM LLY-283 48 hours To evaluate the effect of LLY-283 and TMZ combination treatment on apoptosis. Results showed that the combination treatment significantly increased caspase 3/7 activity, indicating enhanced apoptosis. Res Sq [Preprint]. 2025 Feb 10:rs
GBMNS (GBM12) 6 µM TMZ, 3 µM LLY-283 48 hours To evaluate the effect of LLY-283 and TMZ combination treatment on apoptosis. Results showed that the combination treatment significantly increased caspase 3/7 activity, indicating enhanced apoptosis. Res Sq [Preprint]. 2025 Feb 10:rs
GBMNS (GSC082209) 50 µM 48 hours To evaluate the effect of LLY-283 and TMZ combination treatment on apoptosis. Results showed that the combination treatment significantly increased caspase 3/7 activity, indicating enhanced apoptosis. Res Sq [Preprint]. 2025 Feb 10:rs
GBMNS (GSC040815) 50 µM 48 hours To evaluate the effect of LLY-283 and TMZ combination treatment on apoptosis. Results showed that the combination treatment significantly increased caspase 3/7 activity, indicating enhanced apoptosis. Res Sq [Preprint]. 2025 Feb 10:rs
HEI-OC1 cells 100 μM 2 hours pretreatment followed by co-culture with 30 μM cisplatin for 24 hours To investigate the protective effect of LLY-283 on cisplatin-induced auditory cell injury. The experiments confirmed that LLY-283 could significantly increase cell viability and reduce lactate dehydrogenase (LDH) release, indicating that LLY-283 could alleviate cisplatin-induced damage to HEI-OC1 cells. J Clin Lab Anal. 2022 Feb;36(2):e24176
Normal human astrocytes (NHAs) 1 μM 5 days Minimal response to PRMT5 inhibition Nat Commun. 2021 Feb 12;12(1):979
Human fetal neural stem cells (HFNS) 1 μM 5 days Sensitive to PRMT5 inhibition, EC50 values similar to GSCs Nat Commun. 2021 Feb 12;12(1):979
HSJD-DIPG-007 1 µM 7 days To evaluate the effect of LLY-283 on the viability of HSJD-DIPG-007 cells, results showed that PRMT5 inhibitors significantly reduced cell viability. Sci Rep. 2024 Jan 3;14(1):328
A375 cells 40 nM 72 hours To evaluate the effect of LLY-283 on PRMT5-mediated regulation of MDM4 splicing, results showed that at 40 nM concentration, LLY-283 significantly inhibited the splicing of MDM4 exon 6. ACS Med Chem Lett. 2018 Apr 23;9(7):612-617
MCF7 cells 1 μM 48 hours To evaluate the inhibitory effect of LLY-283 on PRMT5 activity, results showed that at 1 μM concentration, LLY-283 significantly reduced SmBB′-Rme2s levels. ACS Med Chem Lett. 2018 Apr 23;9(7):612-617

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
NSG mice Orthotopic patient-derived xenograft model Oral gavage 50 mg/kg 3 days on, 4 days off weekly cycles for 4 cycles or until endpoint LLY-283 significantly extended the survival of mice and reduced tumor size Nat Commun. 2021 Feb 12;12(1):979
Athymic nude mice HSJD-DIPG-007 orthotopic xenograft model Oral gavage 50 mg/kg 3 days on, 4 days off for 4 weeks To evaluate the therapeutic efficacy of LLY-283 in the HSJD-DIPG-007 orthotopic xenograft model, results showed that LLY-283 did not prolong survival but reduced tumor cell infiltration into the mouse forebrain. Sci Rep. 2024 Jan 3;14(1):328
NOD.CB17-Prkdcscid/NCrCrl mice Intracranial GBM mouse model Oral gavage LLY-283: 50 mg/kg body weight/day; TMZ: 10 mg/kg body weight LLY-283: Administered orally in weekly cycles of 3 days on, and 4 days off, until all the mice in the TMZ-treatment alone group reached the end stage of the study; TMZ: Administered on days 7, 9, 11, 13, and 15 post-tumor implantation. To evaluate the effect of LLY-283 and TMZ combination treatment on tumor growth and survival. Results showed that the combination treatment significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice. Res Sq [Preprint]. 2025 Feb 10:rs
SCID mice A375 xenograft model Oral 20 mg/kg Once daily for 28 days To evaluate the antitumor effect of LLY-283 in vivo, results showed that at 20 mg/kg dose, LLY-283 significantly inhibited tumor growth. ACS Med Chem Lett. 2018 Apr 23;9(7):612-617

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.92mL

0.58mL

0.29mL

14.60mL

2.92mL

1.46mL

29.21mL

5.84mL

2.92mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2
 

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