Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer

Sutherlin, Daniel P.; Bao, Linda; Berry, Megan; Castanedo, Georgette; Chuckowree, Irina; Dotson, Jenna; Folks, Adrian; Friedman, Lori S.; Goldsmith, Richard; Gunzner, Janet L.; Heffron, Timothy P.; Lesnick, John; Lewis, Cristina; Mathieu, Simon; Murray, J.M.; Nonomiya, Jim; Pang, Jodie; Pegg, Niel; Prior, Wei Wei; Rougé, Lionel; Salphati, Laurent; Sampath, Deepak; Tian, Qingping; Tsui, Vickie; Wan, Nan Chi; Wang, Shumei; Wei, BinQing; Wiesmann, Christian; Wu, Ping; Zhu, Bing‐Yan; Olivero, Alan G.

doi:10.1021/jm2009327

Cited by 189 publications

(125 citation statements)

References 33 publications

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“…GDC-0980 is synthesized by substituting the indazole in GDC-0941 for a 2-aminopyrimidine [73] . This substitution also enhances the efficacy of mTOR inhibition.…”

Section: Achievements In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…GDC-0980 is synthesized by substituting the indazole in GDC-0941 for a 2-aminopyrimidine [73] . This substitution also enhances the efficacy of mTOR inhibition.…”

Section: Achievements In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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“…Another reason for the limited success is the presence of feedback loop between mTORC1 and AKT in certain tumor cells. It seems that mTORC1 inhibition by rapalogs fails to suppress a negative feedback loop that results in phosphorylation and activation of AKT [48,[53][54][55]. These limitations have led to the development of the second generation of mTOR inhibitors known as ATP-competitive mTOR kinase inhibitors [55].…”

Section: Clinical Indications Of M-tor I In Nontransplant Patients Anmentioning

confidence: 99%

m-TOR Inhibitors in the Current Practice

Alalawi¹,

Sharma²,

Halawa³

2017

J Clin Exp Nephrol

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Abstractfor long time, calcineurin-inhibitors (CNIs) was the best broadly used immunosuppressant in organ transplantation; since it had proven its efficacy in the reduction of acute rejection episodes and early graft loss, though their use in the long-term, are associated with chronic allograft nephropathy (CAN), besides it increases the cardiovascular risks such as diabetes, hypertension, and dyslipidemias. Moreover, CNIs in combination with other immunosuppressant's increases the risk of fatal infections and malignancy. Ultimately the introduction of the mammalian focus of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus in 1990s, had changed the face of transplantation and conveyed a great hope to transplant physicians as an innovative class of effective immunosuppressants with a unique mechanism and less nephrotoxic effects (1-6).In this review article we will try briefly to elicit the clinical indications, advantage and disadvantage of m-TOR inhibitors over other immunosuppressant's medications and their clinical indications inside and outside the transplant field.

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“…Incorporation of this heterocycle into further derivatives would permit a search for more potency through more lipophilic amines, without departing from the ideal logD range or increasing the molecular weight beyond 500, as has recently been described by Genentech-Piramed. 29 It is interesting that, as yet, none of the students have proposed making GDC-0941 ( Figure 6), 23 which was the PI3K inhibitor taken into development. This is because the sulfonylpiperazine does little to improve aqueous solubility and is thus an unattractive choice of amine.…”

Section: Chemistry Achievements and Challengesmentioning

confidence: 99%