AMG 232, a MDM2-p53 Inhibitor

Treatment with 2 caused time dependent induction of p21 mRNA in SJSA-1 tumor xenografts
Female athymic nude mice were implanted subcutaneously with 5 × 106 SJSA-1 cells. When tumors reached ∼175 mm3, 50 mg/kg of 2 or vehicle was administered QD for 4 days. Mice were sacrificed on day 4 at 1, 2, 4, 8, and 24 h postdose(n = 5/group).
Cocrystal structure of AM8553(1) bound to human MDM2
Cocrystal structure of 1 bound to human MDM2 (17−111) at 2.0 Å resolution and depicting proposed electrostatic interactions with H96 and G58 “shelf” region (circled). White labels indicate the positions normally occupied by key p53 residues. MDM2 residues H96, G58, M62, N59, and F55 are labeled in yellow
Treatment with 2 inhibited the growth of SJSA-1 tumors
SJSA-1 cells (5 × 106) were implanted subcutaneously into female athymic nude mice. Treatment with vehicle or 2 at 7.5, 15, 30, or 60 mg/kg QD by oral gavage began on day 11 when tumors had reached ∼200 mm3 (n = 12/group).
Inhibition of SJSA-1 tumor xenograft growth by compound 25
SJSA-1 cells (5 × 106) were implanted subcutaneously into female athymic nude mice. Treatment with vehicle or 25 at 25, 50, 100, or 200 mg/kg q.d.
Modification of the Carboxylic Acid
Fully Functionalized Piperidinone Derivatives
Co-crystal structure of 23 bound to human MDM2
Comparison of 25 and 26 in Selected PKDM Assays
X-ray cocrystal structure of 10 bound to MDM2
Two strategies: (i) optimization of the observed binding mode by occupying the Leu26 pocket and enhancing the F55 interaction (ii) redesign of the morpholinone pharmacophore to induce a different binding mode in which the haloaryl rings are directed into the Trp23 and Leu26 pockets
Cocrystal structures of AMG232 bound to human MDM2
Binding mode of 1 based on the cocrystal structures of 17 bound to human MDM2 (17−111) (PDB code 4OAS).15 MDM2 binding pockets are labeled (by p53 side chain) in white. MDM2 residues H96, G58, M62, N59, and F55 are labeled in yellow.
PD study of compound 25
Female athymic nude mice were implanted subcutaneously with 5 × 106 SJSA-1 cells. When tumors reached ∼175 mm3, (a) 25 or vehicle was administered orally once. Mice were sacrificed at 1, 3, 6, 9, 16, and 24 h postdose (n = 5/group). (b) Vehicle or 30, 100, or 300 mg/kg 25 was administered orally once.
Optimization of F55 Interaction
Strategy to project a hydrophobic substituent into the Leu26 pocket
Modulation of the Binding Mode
SAR of Morpholinone Analogues .
Initial Modification of the N-Alkyl Group
Sulfonamide and Reverse Sulfonamide Piperidinone Derivatives
Sulfone Piperidinone Derivatives
Combination of Alkyl Groups at R1 and R2
Discovery of the novel piperidinone lead 11
6
Discovery of AM8553 & AMG232
The P53 pathway
P53 and MDM2 autoregulatory mechanism
Cocrystal structure of p53 with MDM2 & leading compounds
HTRF 0.018 ±0.004 μM HTRF(15%HS) 0.089 ±0.012 μM
AMG 232, a MDM2-p53 Inhibitor in Clinical Development
J. Med. Chem. 2012,55, 4936-4954 J. Med. Chem. 2013,56, 4053-4070 J. Med. Chem. 2014,57, 1454-1472 J. Med. Chem. xxxx, xx, xxx-xxx
Science 1996, 274, 948−953.
Compounds based on docking
Compounds HTRF IC50(μM) >30 Compounds HTRFIC50(μM) >30
>30
1.8±0.1
14.1±0.4
(10)
1.0±0.1
5.4±0.3
>30
2.0±0.1
பைடு நூலகம்
C3 Me Piperidinone Derivatives
Comparison of 25 and 29
Inhibition of SJSA1 tumor xenograft growth by 29
SJSA-1 cells (5 × 106) were implanted subcutaneously into female athymic nude mice. Treatment with vehicle or 29 at 25, 75,150, or 200 mg/kg q.d. by oral gavage began on day 11 when tumors had reached ∼200 mm3 (n = 10/group).
X-ray cocrystal structure of 10 (cyan) bound to MDM2. p53 binding pockets are labeled in white, MDM2 residues in yellow. Resolved water molecules are depicted as red spheres
Mouse PK &PD of Analogue 27
Cocrystal structure of 28 bound to MDM2
Potency of Analogues 31−35
Model of proposed binding mode of lead compound
Exploration of the N-Alkyl Group
0.070 ±0.010 μM 0.96 ±0.09 μM
X-ray cocrystal structure of p53 (green) with MDM2 (tan), p53 residues and corresponding binding pockets are labeled in white.