Selective and Potent Morpholinone Inhibitors of the MDM2–p53 Protein–Protein Interaction

Abstract

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

“…Optimization of this series was guided by the knowledge gained in the piperidone series [39]. Comparison of 16b with the equivalent piperidone showed a 5-10-fold loss of potency, but better stability in hepatocytes derived from human and other mammalian species.…”

A therapeutic patent overview of MDM2/X-targeted therapies (2014–2018)

“…Importantly, in recent years, several representative compounds have successfully passed through pre-clinical studies and entered the clinical trials (reviewed in [22], see also Tables 1-3). These include the nutlin-3a derivative RG7112 [92] and its pyrrolidine relative, RG7388 (idasanutlin) from Roche [27], the piperidinone compound AMG-232 from Amgen [93,94], the bicyclic-core compounds CGM097 and HDM201 from Novartis [48,95], three spiroindolinone derivative compounds, SAR405838 from Sanofi [96], APG-115 from Ascentage Pharma Group Inc [97]., DS-3032b from Daiichi Sankyo [98], a multicyclic-core compound BI 907828 from Boehringer Ingelheim [99], and a stapled peptide ALRN-6924 from Aileron Therapeutics [100]. Among these, RG7388 (idasanutlin, RO5503781) is now most advanced, as it has recently progressed to the phase III clinical trials in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia [22].…”

Reviving the guardian of the genome: Small molecule activators of p53

“…Yu et al, 2014; Zhuang et al, 2011), which all demonstrate nanomolar binding affinities to MDM2 and with one pyrrolidinone exhibiting dual MDM2/MDMX activity (Zhuang et al, 2012) and one pyrrolopyrazole seemingly active against both MDM2 and the NF-κB complex (Zhuang et al, 2014), a different cancer-related pathway (DiDonato, Mercurio, & Karin, 2012). Perhaps most promising are a series of piperidonones (AM-8553, AM-7209, AMG 232) and morpholinones (AM-8735) developed from Amgen laboratories that exhibit exceptional pharmacokinetic properties, such as low clearance rate, long half-life, and high oral bioavailability (Gonzalez-Lopez de Turiso et al, 2013; Gonzalez, Eksterowicz, et al, 2014; Rew et al, 2012; Rew et al, 2014; Sun et al, 2014). One piperidonone, AMG 232, is currently recruiting for Phase I/II clinical trials for advanced solid tumors or multiple myeloma as a standalone drug (NCT01723020), AML in combination with trametinib, a MEK1/2 inhibitor, (Mandal, Becker, & Strebhardt, 2016) (NCT02016729), and metastatic melanoma in combination with trametinib and dabrafenib (NCT02110355).…”

“…One piperidonone, AMG 232, is currently recruiting for Phase I/II clinical trials for advanced solid tumors or multiple myeloma as a standalone drug (NCT01723020), AML in combination with trametinib, a MEK1/2 inhibitor, (Mandal, Becker, & Strebhardt, 2016) (NCT02016729), and metastatic melanoma in combination with trametinib and dabrafenib (NCT02110355). Researchers from Amgen laboratories continue to make chemical modifications to further optimize lead compounds and improve both potency and pharmacokinetic properties (Gonzalez, Li, et al, 2014; M. Yu et al, 2014).…”