Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Delorme, Cécile; Karlsson, Andreas; Rak, Alexey; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean‐Christophe; Abecassis, Pierre Yves; Lejeune, Pascale; Vincent, Loı̈c; Bonnevaux, Hélène; Nicolas, Jean Paul; Bertrand, Thomas; Marquette, Jean Pierre; Michot, Nadine; Bénard, Tsiala; Below, Peter; Vade, Isabelle; Chatreaux, Fabienne; Lebourg, Gilles; Pilorge, Fabienne; Angouillant-Boniface, Odile; Louboutin, Audrey; Lengauer, Christoph; Schio, Laurent

doi:10.1021/jm300241b

Cited by 52 publications

(50 citation statements)

References 34 publications

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“…Insights provided by these structures are crucial for the development of novel strategies aimed at creating more effective chemotherapeutic interventions against tumors harboring these mutations. Design of isoform-specific and mutation- specific inhibitors will be helped by the availability of inhibitor complexes of PI3Kα as well of those of other PI3K isoforms (Mandelker et al 2009; Berndt et al 2010; Certal et al 2012; Hon et al 2012; Murray et al 2012). …”

Section: Discussionmentioning

confidence: 99%

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

et al. 2014

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PI3Kα, a heterodimeric lipid kinase, catalyzes the conversion of phosphoinositide-4,5-bisphosphate (PIP2) to phosphoinositide-3,4,5-trisphosphate (PIP3), a lipid that recruits to the plasma membrane proteins that regulate signaling cascades that control key cellular processes such as cell proliferation, carbohydrate metabolism, cell motility, and apoptosis. PI3Kα is composed of two subunits, p110α and p85, that are activated by binding to phosphorylated receptor tyrosine kinases (RTKs) or their substrates. The gene coding for p110α, PIK3CA, has been found to be mutated in a large number of tumors; these mutations result in increased PI3Kα kinase activity. The structure of the complex of p110α with a fragment of p85 containing the nSH2 and the iSH2 domains has provided valuable information about the mechanisms underlying the physiological activation of PI3Kα and its pathological activation by oncogenic mutations. This review discusses information derived from x-ray diffraction and theoretical calculations regarding the structural and dynamic effects of mutations in four highly mutated regions of PI3K p110α, as well as the proposed mechanisms by which these mutations increase kinase activity. During the physiological activation of PI3Kα, the phosphorylated tyrosine of RTKs binds to the nSH2 domain of p85, dislodging an inhibitory interaction between the p85 nSH2 and a loop of the helical domain of p110α. Several of the oncogenic mutations in p110α activate the enzyme by weakening this autoinhibitory interaction. These effects involve structural changes as well as changes in the dynamics of the enzyme. One of the most common p110α mutations, H1047R, activates PI3Kα by a different mechanism: it increases the interaction of the enzyme with the membrane, maximizing the access of the PI3Kα to its substrate PIP2, a membrane lipid.

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Section: Discussionmentioning

confidence: 99%

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

et al. 2014

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“…AKT phosphorylation on Ser473 or Thr308 (pAKT-Ser473 or pAKT-Thr308) was measured using a sandwich immunoassay kit (Meso Scale Discovery), as recommended by the manufacturer and described previously (22,23). IC 50 values were calculated using the Biost@t SPEED internal software and a four-parameter logistic model.…”

Section: Akt Phosphorylation Assaysmentioning

confidence: 99%

“…SAR260301 inhibition of AKT-Ser473 phosphorylation was evaluated in cellular systems relevant for PI3Ka, PI3Kb, PI3Kg, and PI3Kd (PIK3CA-mutated H460 lung tumor cells, MEF-3T3-myr p110b, C5a-stimulated RAW 264.7 mouse macrophages, and MEF-3T3-myr p110d, respectively; ref. 23). Selectivity against VPS34 was investigated in GFP-2xFYVE and GFP-LC3 HeLa-expressing cells: SAR260301 at 10 mmol/L did not induce GFP-FYVE relocalization to cytoplasm and did not prevent starvation-induced autophagy ( Supplementary Fig.…”

Section: Sar260301 Is a Selective Pi3kb Inhibitor In Cellular Assaysmentioning

confidence: 99%

Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor

Bonnevaux

Lemaitre

Vincent

et al. 2016

Molecular Cancer Therapeutics

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Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity of melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined with MAPK inhibitors in the treatment of melanoma exhibiting concurrent genetic abnormalities, overlapping adverse events in patients limit optimal dosing and clinical application. With the aim of specifically targeting PTEN-deficient cancers and minimizing the potential for on-target toxicity when inhibiting multiple PI3K isoforms, we developed a program to discover PI3Kb-selective kinase inhibitors and identified SAR260301 as a potent PI3Kb-selective, orally available compound, which is now in clinical development. Herein, we provide a detailed biological characterization of SAR260301, and show that this compound has outstanding biochemical and cellular selectivity for the PI3Kb isoform versus the a, d, and g isoforms and a large panel of protein and lipid kinases. We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models. Combination treatments were very well tolerated, suggesting the potential for a superior safety profile at optimal dosing using selective compounds to inhibit multiple signaling pathways. Together, these experiments provide a preclinical proof-of-concept for safely combining inhibitors of PI3Kb and BRAF or MEK kinase modulators to improve antitumor activity in PTEN-deficient/BRAF-mutant melanoma, and support the evaluation of SAR260301-based combinations in clinical studies. Mol Cancer Ther; 15(7); 1460-71. Ó2016 AACR.

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“…[31][32][33] The examination of the binding mode and properties of compounds 2-4 led to the following conclusions: while it has been difficult to associate the nature of the N-substituent and the selectivity profile of the corresponding molecules, the position which points towards the entrance 12 of the binding site constitutes a good target to improve in vitro ADME properties. Modifying the hinge binder moiety [15][16][17] has already resulted in an enhanced selectivity profile and further modifications might bring additional selectivity and potency. Similarly, it might be possible to replace the trifluoromethyl moiety to either gain Vps34 potency and/or lose activity against the other lipid kinases.…”

Section: Vps34 X-ray Structures Of Compounds 2 3 Andmentioning

confidence: 99%

“…However, preference was given to compound 3 due to better metabolic profile and a higher potential for the side chain exploration while maintaining potency. 17 We next turned our attention to the morpholine hinge-binding group while fixing the (2S)-trifluoromethyl substitution to maintain GFP-FYVE cellular potency. As depicted in Figure 4, the hinge-binder region is a lever to modulate selectivity against other kinases.…”

Section: Vps34 X-ray Structures Of Compounds 2 3 Andmentioning

confidence: 99%

Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

Pasquier¹,

El-Ahmad²,

Filoche-Rommé³

et al. 2014

J. Med. Chem.

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Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

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Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Cited by 52 publications

References 34 publications

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

Activation of PI3Kα by physiological effectors and by oncogenic mutations: structural and dynamic effects

Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor

Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

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