AA-115

Cas No.:	1818393-16-6
Chemical Name:	4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid
Synonyms:	APG-115;15QAU0SI9J;4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid;APG115;APG 115 [WHO-DD];BDBM50237739;NSC831270;(3'R,4'S,5'R)-4-((6-Chloro-2-oxo-1,2-dihydro-spiro(indole-3,3'-pyrrolidin)E-4'-(3-chloro-2-fluoro -phenyl)-1'-ethyl-spiro(cyclohexane-1,2'-pyr
SMILES:	ClC1C([H])=C([H])C2=C(C=1[H])N([H])C([C@@]12[C@@]([H])(C2C([H])=C([H])C([H])=C(C=2F)Cl)[C@]([H])(C(N([H])C23C([H])([H])C([H])([H])C(C(=O)O[H])(C([H])([H])C2([H])[H])C([H])([H])C3([H])[H])=O)N(C([H])([H])C([H])([H])[H])C21C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])=O
Formula:	C34H38Cl2FN3O4
M.Wt:	642.5876
Purity:	>98%
Sotrage:	2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO
Publication:	[1]. Angelo Aguilar, et al. 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J Med Chem. 2017 Apr 13; 60(7): 2819–2839. [2]. A W Tolcher et al, A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors, Ann Oncol. 2019 Feb 1; 30(Supplement_1). pii: mdz027. [3]. Hanjie Yi ea al, A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma, J Exp Clin Cancer Res. 2018 May 2;37(1):97. [4]. Chen H, et al. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. Oncotarget. 2017 Jun 27;8(26):43008-43022.

Description:	AA-115 (APG 115) is a potent and orally active MDM2 inhibitor with Ki <1 nM, potently inhibits SJSA-1 cell growth with IC50 of 60 nM; exhibits IC50 values of 38, 18, and 104 nM in the RS4;11 acute leukemia, LNCaP prostate cancer, and HCT116 colon cancer cell lines, respectively; effectively inhibits tumor growth and causes no or minimal weight loss.
Target:	IC50: 3.8 nm (APG-115)[1]
In Vivo:	APG-115 (Delivered orally; 100 mg/kg; once daily; 10 days) enhances radiation antitumor effect in gastric adenocarcinoma in vivo[3]. Animal Model: Four-week-old male BALB/c athymic nude mice with MKN45 cells[3] Dosage: 100 mg/kg Administration: Deliverer orally; once daily; 10 days Result: Decreased xenograft tumor growth.
In Vitro:	APG-115 (0.001-100 μM; 72 hours) inhibits cell proliferation in concentration-dependent manner, with IC50s of 18.9 ± 15.6 nM and 103.5 ± 18.3 nM respectively in AGS and MKN45 cells[3]. APG-115 (0.02 μM, 0.2 μM; 48 hours) enhances the anti-proliferative effect of radiotherapy at different radiation dose[3]. APG-115 (0.02 μM, 0.2 μM; 48 hours) affects progression by inducing cells arrested at G0/G1 phase in AGS and MKN45 cell with wild p53[3]. APG-115 (0.02 μM, 0.2 μM; 24 hours) activates p53 to enhance radiosensitivity in AGS and MKN45 cells; stable knockout of p53 abrogates expression of MDM2, p53, p21, PUMA, BAX, Cleaved-caspase3, γH2AX[3]. APG-115 (0.3 μM, 1 μM, 3 μM, 10 μM; 24 hours) leads to a concentration-dependent cell cycle arrest in G2/M phases and a decreasing in S-phase in p53 wide-type cell lines (TPC-1, KTC-1)[4]. Cell Proliferation Assay[3] Cell Line: AGS and MKN45 cells Concentration: 0.0001 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, 100 μM Incubation Time: 72 hours Result: Inhibited cell proliferation in a concentration-dependent manner. RT-PCR[3] Cell Line: AGS and MKN45 cells Concentration: 0.02 μM, 0.2 μM Incubation Time: 48 hours Result: Elevated MDM2, p21, PUMA and BAX mRNA expression. Cell Cycle Analysis[3] Cell Line: AGS and MKN45 cells Concentration: 0.02 μM, 0.2 μM Incubation Time: 48 hours Result: Arrested cells at G0/G1 phase. Western Blot Analysis[3] Cell Line: AGS and MKN45 cells Concentration: 0.2 μM Incubation Time: 72 hours Result: Enhanced expressions of MDM2 and p53, stable knockout of p53 abrogated them. Apoptosis Analysis[4] Cell Line: DePTC p53 wide-type cell line: TPC-1 cells, KTC-1 cells Concentration: 0.3μM, 1μM, 3μM, 10 μM Incubation Time: 24 hours Result: Reduced cell population in S-phase, whereas accumulation of cells at G2/M phases.
References:	[1]. Angelo Aguilar, et al. 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. J Med Chem. 2017 Apr 13; 60(7): 2819–2839. [2]. A W Tolcher et al, A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors, Ann Oncol. 2019 Feb 1; 30(Supplement_1). pii: mdz027. [3]. Hanjie Yi ea al, A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma, J Exp Clin Cancer Res. 2018 May 2;37(1):97. [4]. Chen H, et al. Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells. Oncotarget. 2017 Jun 27;8(26):43008-43022.