ChemicalBook CAS DataBase List 1451750-73-4

1451750-73-4

Name	Pentanedioic acid, 2-hydroxy-4-methylene-, 1,5-diethyl ester
CAS	1451750-73-4
Molecular Formula	C10H16O5
Molecular Weight	216.23
MOL File	1451750-73-4.mol

Chemical Properties

Boiling point	300.3±37.0 °C(Predicted)
density	1.118±0.06 g/cm3(Predicted)
storage temp.	2-8°C
form	oil
pka	12.57±0.20(Predicted)
color	colorless to yellow

Hazard Information

Uses

TETi76 is an orally active TET family inhibitor with IC50 values ??of 1.5, 9.4 and 8.8 μM for TET1, TET2 and TET3, respectively. TETi76 competitively binds to the active site of TET enzymes, reduces cytosine hydroxymethylation and restricts clonal growth of TET2 mutants in vitro and in vivo, but does not affect the growth of normal hematopoietic precursor cells. TETi76 can be used for leukemia research[1].

Biological Activity

TETi76 diethyl ester is a cell-permeant diester form of the α-KG-competitive and hightly selective TET1/2/3 dioxygenase inhibitor TETi76 acid (TET2 cat. domain Kd = 0.3 μM; no potency against 16 other αKG/Fe2+-dependent enzymesincluding closely related RNA dioxygenase FTO). TETi76 ester downregulates cellular 5-hydroxymethylcytosine (5hmC) levels (IC50 = 20-37 μM; K562MEG01SIGM5OCI-AML5MOLM13)exerts preferential cytotoxicity in TET-deficient cultures (TET2/3-knockout K562 LD50 ~10 μM vs wt K562 LD50 ~40 μM) and significantly reduces TET2-deficient SIGM5 tumor burden in mice in vivo (50 mg/kg p.o.).

in vivo

TETi76 (50 mg/kg; oral; 5 days per week; 3 months) has no significant effect on the total body weight and overall blood cell counts of mice in Tet₂^+/+, Tet₂^+/-, and Tet₂^-/- mouse models on the C57BL6 background, but reduces the spleen size of Tet₂-deficient mice in a gene dose-dependent manner^[1].
TETi76 (25 mg/kg; ip; once daily, 5 days per week; 4 weeks) limits the proliferative advantage of Tet₂^?/? (CD45.2) cells in the C57BL6 CD45.1 Pep Boy mouse model (lethally irradiated and transplanted with mixed bone marrow cells) without affecting the proportion of mice receiving Tet₂^+/+ (CD45.2) cells^[1].
TETi76 (50 mg/kg; oral) significantly reduces tumor burden in the immunodeficient NSG mouse model (subcutaneously implanted with the human TET₂^?/? leukemia cell line SIG-M5)^[1]).

Animal Model:	C57BL6 mice (sex not specified, weight not specified, age not specified) with Tet₂^+/+, Tet₂^+/? and Tet₂^?/? genotypes + Mouse model for observing the effect of TETi76 on spleen size and general health^[1]
Dosage:	50 mg/kg
Administration:	Oral administration, 5 days per week, for 3 months
Result:	Did not show significant changes in the overall body weight and overall blood counts of the mice compared with the placebo group. Decreased the spleen sizes of Tet₂-deficient mice in a gene dose-dependent manner.

IC 50

TET1: 1.5 μM (IC₅₀); TET2: 9.4 μM (IC₅₀); TET3: 8.8 μM (IC₅₀)

References

[1] Yihong Guan, et al. A therapeutic strategy for preferential targeting of TET2-mutant and TET dioxygenase–deficient cells in myeloid neoplasms. Blood cancer discovery 2.2 (2021): 146-161. DOI:10.1158/2643-3230.BCD-20-0173

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