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    New and potential therapies for the treatment of Breast Cnacer An update for oncologists

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    New and Potential Therapies For The Treatment of Breast Cnacer An Update For Oncologists-VARRUCHI - 25.05.2015

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    New and potential therapies for the treatment of Breast Cnacer An update for oncologists

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    158 2249-4073; eISSN 2821-0268 Current Trends in Biotechnology and Chemical Research ‘Reeve: January 21,2018; cepted May 25,2018 New and potential therapies for the treatment of breast cancer: An update for oncologists Var Ruchi Sharma’, Daljit K Sharma* ,Navnit "Anil K, Sharma’ and Navneet Batra” "Deparment of oteehnoogy, Mahar Markindsshwar Unive, Mullns-Arala Haryana) nds 33207 "Depurment of Science, Gurl Global School, Manimaja, Neat IT Puk. Chang. ind "Deparment of etechncogy, CCOSD Cllge Sec 12 Chandiguh nd 160022 Abstract Breast cance isthe most common and precarious kind of “cancer in womenlmen and isthe principal eause of cancer related deaths. The uninhibited multiplication of abnoeral tissue nthe beas ithe major cause of Breast cancer Abo such cancerous ells can cause futher damages in the body Breas cancer i caused mainly ue to mutaton in _genes like PAK/AKT, mTOR ete. Number ofnovel therapies have come forward in cumers years with clinical ial data representing safltyeicacy forthe breast cancer patients. Breast cancer tues incided inthis ace are om the ‘year 2010 onwards along with the information of novel potential drugs wbich are either in Phase I or Phase I of ‘development. Introduction Breastcancerdevelopsirom breasttissueusally fom inner lining of milk supplier mi cuts othe lobules. The main signs of breast cancer incles arp in the breast nipple discharge, redness of sin, change in breast shape or size, Iymph node sling. Alloverthe worldbreas cancer isthe ‘mos commoncance, speciallyinUSitisthe second most ‘common cancer afer skin cancer. In breast cancer both men and women canbe the tage. Today duet weatment fdvancement the breast cancer survival rates have been, increased. Asconly the weatment of this typeof cancer only “dependsonthestage andthe size ofbreastcancercus issue. In the drug development process for a drug o bein the ‘market both Preclinical and lineal suds are conducted Inwhich the clinica tials corduction is done by some ‘expert team of doctors oF by medical professionals, Jvesigalor, pharmaceutical companies, medical centers, “Corresponding Author: Dr. Navneet Batra, Department of Biotechnology, GGDSD College, Sec 32 ‘Onanigar india 60032. Te: +91-9417850670; Email ID: nayneot0S@ymai.com and various hospitals and also by some non-profit ‘organization at various locationsalloverthe wodd. Inthispa or insuchirialsthe chug is goingto be ested atts ‘various levels using various parameters, Uke saetyeficacy of a drug before its going to be used by general public. Upon the completion ofthese clinial tale the ful Information cr results represented at variousresources ike Joumals, Clnicalals gov, Pubmed, Various al regites, the meting of companies, inthe conferences of medical protessonalset In this review anicle we have tried to put some use Jiformationéata of some emerging drugs forthe weaiment of breast cancer. The purpose ofthis review to provide the information on the new therapies thet is curently in ddevelopmentforthetreatmentefbreas cances, Methods Dataretreved using clnicalials.gov, Pubmed, journal and medical conferences agnine breast cancer and tried fn finding ou the studies of new emerging drugsagentsiorthe tweaiment of breast cancer helpful for ancologiss. 1] Search ofthe ales available, yer 2010 onwards, Using eynord to identity randomized, controlled studs for Breas Cancer 3]. Emerging inhibitors forthe Treatment breast cancer LAL161 (Novartis: ‘Molcular inhibitor developed by Novartis which has an feflecve ant4umour activity and is antagonist of the Inhibitor of apoposis AP) proteins [45] LCLI6t pesos as an fective radiosenstizer [6]. LCLI6I assesment pertrmed using vple negative breast cancer patients ia phase Il randomized ard open-label ral (NCTO161 7668) Pationtsincladed inthetil were 210in umber Patientsia the tial were given as: paclitaxel (00 mp/m2hveck) {C1161 (1800 me/weeh forthe period oF 12 weeks. Among diferent percentages pathological complete response fchieved as: 16% patients In fhe combination arm and 165% inthe contol arm. The common unfavorable elects ‘Cuncot Trends in Biotechnology and Chemical Resarch [January-June 2016] VoL 6 sue 1 Breast Cancer natced are diathea, alopecia, pyesa, fatigue, nausea, rash, ncutopenia, headache. Some potetal efficacy signs from Necadjuvant LCLY61 wih paclitaxel shown ~30% of ppaiens, also with some prominent toxicity with weebly ‘dose of 1800 mg (7) GanetespibSTA-9090) A molecular inhibitoe rom heat shock protein 90 (Hsp 90) This inhibior Is in Phase Il of is development. Acs as molecular chaperone forthe maturation and establishment ‘of pumorous client proteins. Canctespib (STA-9090) dealing induces constant deterioration of oncogenic signaling pathways. Even a small exposure encourages ‘oporesion of HER? levels in cells motivated by the same receptor Even the small weatment of Ganetespib weakens ‘utile client proteins and oncogene signaling pathways ‘ko persuade and maotain oppression of HER? level 6 monihs. 7 ‘weeks (95% confidence interval (Cl, 7-19) median progression-free survival, 46 weeks (95% Cl, 27-not Spplcable median overall survival In he fist sage study ‘dd not eee the predeinad ceria for overall sponse rate i vastuzumabreactory HERD-posive and TNBC response observed. Ganetspib was well tolerated among ‘the population. [10] aer2t MMLI21 is PBK (hosphoinostide 3.4inase) activator, HER? (human epidermal growth factor recepor 2), andisa hepatocyte growh actor receptor addcedeancer [1] ‘There are three completed studies for MM-121 (NcTO1421472, NCTOI151046and NCTO1209195) Resi forthese audios are: ('NcTO1421472) Patients in phase 2 vial with ER pose, HERZ negative invasive breast cancer or invasive ple nogative beast cancer were randomized for 12 weoks to receive pacltasel with or witheut MM-121 followed by 4 cycles of doxorubicin plus cyclophosphamide and Following surgery ina open-label, randomized. In tal of 196 patents wereranomized In Group 1 HRs}, 96 patents were Eicay Evahtble (EE) ‘out of 101, also the observed the PCR rate the MM-127 ‘reatment and contol arm was as : 7/66 (10.6%, 95% Cl (5.25, 20.3%) compared 1 1/30 (3.3%, 959 C1 (0.6%, 167%). In Group 2 (TN, 85 paions were Eficacy Evaluable (EE) ‘ut of 99 andthe pCR rate inthe MV-121 resiment anc Cineat Trends in Bskchnology and Chemical Research [Janary-e 2016] Vol. 6 Baa ‘cont arm was as: 23/56 (411%, 95% C1 [29.2% 54.1) ‘compared 01429 (48.3%, 95% CII. 8%, 65.6%). [12] (NCTO1151046) Paton inckude posmenopausal women metasatic estrogen’ oF progederone receptor postive (ERs IPR) with breast cancer HER2 negative. 118 patients ‘were included in the stuhy and were given MMA21 + ‘exerestae or placebo + exemestane. Administration of [MM121 orplaecebo orally a 60 minutelV infusion nce a ‘week and exemestane (25 mg) in a randomized, double- blind phase il “Thore occured tended favor of hazard rato (HR) fo PFS of (MM-121 agm (HR 0.75; 95% C1048 — 1.15), in overall population inthe sty though he primary endpoint ofthe Study (HR <0.5) wasurmet. fn Overallsurival datatherels luended favor of the M121 arm (HR O41; 95% Cl [0.13-0.90), aso is point immature (-25% of patients. his (NCTO1209195) Patients with advanced gynecologic and breast cancers treated with combination of MML-121 and ‘wey pacitanel in a phase 1 udy. Atoll of 28 patients platinum resistant gynecologial cancers or HERZ non- ‘overexpressing breast cancer were included in the study, altowasa pharmacologic and pharmacodynamic study. Almost 70% patients were benefited, 48% achieved paral response (PR) and 39% confirmed PR in 2.7 months (ranging fom 1.7 months — 15.1 months) 22% patents acknouledge stable seas (SD) > 4 months witha petiod fof sable disease (6D) > 4 morths, 9% patients have progressivedease PD and 26% emainin std. [14] BP-C! isdeveloped by Meabco AS 8BP-C1 ananti-cancer complex, uoatmen with thiscomplex shows induced apoptosis and tnggered caspase 8 and ceaspace 9. Pro-apoptotic gene (CASPAAPT, TNFRSF21, INFKB2, FADD, BCLIO and CASP8) expression gets amplifed with BP-CI and level of mRNA transcripts of inhibitory apoptotic genes (BCL2LM, BCL2L2 and MAP) {gets lowered. BP-CI is a complex of benzene-poly- arborylie acids with a low concentration of els: ‘diameineplatinar i dichloride. (13) A Phase 1 Study (NCTO1861509) entitled “Pharmacokinetic, Pharmacodynamic and Interleukin Profile of Iriramusculatly Administered BP-C1 in Women ‘With Metastatic Breast Cancey,istecutngpatients A randomized, double-blind and phase tral (NCT02783794) was conducted in 32 patients with rmetatatc reas cance. In tis study patents were treated ‘with BP.C1 or placa am BP-C1, 0.05% namuscultly dose of 0.035 mg/kg body weight (0.7 mg), weated ‘once daly, he eatment continued for 32 days. There ‘occured ierease in BP-CI group for about 24% ard in Breast Cancer placebo group about 14.3%. In Soll Tumors there was a Significant diference in favor of 8P-C1 regarding Response Evaluation Criteria, The patentsreceiving BP-C1 treatment for 64 days continuously of which 68.4% were as responders, In BP-C1 group sum CTC-NCI toxicity score increased non-sgnifiarily. On other hand patients receiving BP-C' for 64 days toxicity score gts reduced at ‘day 48, but again at day 64 it gets increased, bythe last ‘week there weatment problem linked to breast cancer like painesegetsreduced.16) YE-A64 isa novel, non-steroidal and selecive inhibitor of P45UCI7ICYPI7)-17, 20 lyase) developed by Inpocrin Pharmaceuticals In. im phase forthe treatment of breasteancee [171 “Thetialentiled“APhase 1/2 Open-Label Study to Evakite the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efcary of V-A6t in Patients Wis Advanced Breas Cancer” (NCTO2500446) is curently recruiting patients GDC-0941 is developed by Genertech and isan orally bioavailable clase | selective PLIK inhibtor ® inducer apoptorie and reduced levels of pA, pPRASHO, and pS. ino} “Til entiled*A Phase Ml Tal of GOC-094) (a PEK Inhibitor) in Combination With Cisplatin in Pats With AAndeagen Receptor Negative Triple Negative Metastatic Breast Cancer” was terminated as company stopped production of study dug due 10 excessive toxics. INcTO1918506) “al emit “A Phase , Randomized Study of PaclRavel ‘With GDC-0941 VersusPaciaxel With Placebo in Patiens With Locally Recurrent or Metatatic Breast Cancer's -losed with 197 patients. (NCTO1740336) The study ented “PIPA: A Phase Ib Std to Assess the Salty, Tolerability and Efficacy of the PIEK Inhibiors, Tasolisib (GDC-0032) or Pictlisib (GDC-0941), in Combination With PAlbociclib, With the Subsequent Aktion of Fulsestrant in PIK3CAHmutant Brest Cancer” (§NCT02380842) is reciting patients with satus with a target of 93 patients. The studies (NCT0O960960), (NCTO23898421, (§NCT00928330) are competed and data of the results of these studiesispresentedbelow: “Thetrial entitled “APhae lb, Qper-Label, Dose-Ecalation Study of the Safely And Pharmacology of Pi-Kinace Inhibitor GDC-0941 In Combination With Paclitaxel, With and Without Bevacizumab or Tastuzumab, And With Letrezole in Patients With Locally Recument Ox Metaaatic Breast Cancer” (NCTOO960960) enrolled 71 patents and at ‘dose ranges of up to 330 mg atthe"S+2" dosing schedule, GDC-0941 was generally welliolerated in combination with paclitaxel with or without bevacizumab or ‘rastuzumab and exists anitumor activi [19] The sudy entitled “A Phase tb, Open Label Study of the Safety, Tolerability, Pharmacokinetics, and Activity of “raskzumab and TrastuzumabMCC-DMI Administered Ineavenously and GDC.0981 Administered Orally to Patents With HER2-Postive Metasatic Breas Cancer Who Have Progressed on Previous Tastszumab-Based Therapy” ('NCT00928330) enrolled 57 patients. The combination ‘therapy (rastuzumab emiansine) and! (pertzumab) 98 ‘wall olerated but the pharmacokinetic properties remain Unchanged. No safety concerns were obtained and “combined therapies exvbed anti-cancer act [20] AC215 an HDACH-electiveinhibior isdeveloped by ‘Acetyon Pharmaceuticals ands in phase I development. ACY-I215 at pharmacologically active doses, mainly Inhibits tne acenlation oftbulin compared with stones Hand ,confimingitsHDACE selectivity. [21 The tral entitled “A phase 18 study of ACY-1215 in ‘combination with Nab-paclitaxel in Unresectable oF Metastatic Beeast Cancer” is curently fecruting patients at vatious centers. (NCTO2632071) AAZDS363 is AKT pron kinase inhibitor which i in thas forthe team of brea cancer and is developed by Asrazeneca.Thisinhbiorinhied al AKT ftom and inhibited phosphorylation of AKT subsats in eels and theelte nibs the growth of mor els troduced Bhosphnyion of the AKTHMTOR sutates PRASI, Gsxopands6k. The teatment with AZD5363 inhibit the activity of AKT that results in upregulation and activation of RTKs, includingIGF-IR andlrsR upregulationofFoxOa and Ra mNAsas well as FoxO- and ER dependent wansrition of IGFLand iGFigands (22,23), ‘The AZD5363 trials (NCTO2077569, NCTO2423603, 'NCTO1992952, NCTO1525286) are ongoing and for more information aboutthese suis, refer Table 2 PF.03004014 fs developed by Pfizer. tis a reversible gamma secrease inhibitor which locks the activity of [Notch receptor when binds to gama secrelase and induce the apoptsis and reduce the production of amyloid-beta (Abeta. 24) This molecule alo inhibts maturation of Notchelaed T and Sell. [25] In vivo, it has been observed PF-0308401-4induce apopios, antiproiferation, impaired tumor vasculature, reduced tumor cell self. fenewal ability and decreased metasass activity. in vito, the molecule exhibited activity against formation of endothelial celltube, migration oftumor clan formation lofrmamenosphere [26,27], Shama oa ‘Summary of randomized, contol sues for AZDS363 in patients with breast cancer Table 2: Randomized, contlled wi for AZDS363 in pations with breast cancer NCT Number Pee ea NcrTo20775%9 | Randomized, Pains will wcene: Stage | To asessthe ‘nied " Pharmacodynamics, ieazbs305 a80mgor [void ect ot | inom Esogen ceptor [are Asignmont | paceborwice daly! | AZD3363 on makers postive beam Doutie blind |esing or and 1/2 days | ars -paiferaion ances, Pscebo-onatied | does) the At pty Sitge 2: AZDS263 360mg or 240mg sal orl dosing or Aan days dose ‘Ner01625286 | Randomized Paral [Paes will woke Foes he ty aed [lea tr Assignment, Dable | dete doses and eteacy ofditerent | Canada, Pains with Bind, Paccbo-| AZD5363 combination | doses and schedules ot | Czech vanced or ceed wihpactanc AZDSi68. Repu, measic benz | Saeytcacy sd France, cance sap, Sou ‘Mexico, Peru, Singapore, Spain Unto nga NeToIG0; | Randomized, Pall | Paes willberardonised | Proyrestonice | Unted " JAmigrmet, able | wi ether ofthe Arms | sunival nga Tiple Negative | ind, Porch | Pachimnel x Placebo OR | Tne Frame Date of Adhanced or come, ecacy | Paclael +1 Az05363. | andoriaiono dae MetaatiEreat | stad ot fnt meu cance progressioner death (tie canrangeon ears) teks and 32 wea) NcTo195%852 | Randomized Parallel, Froeaablih he MTD | Unied we Assignment, Double Joraz05363im | Kingdom Poumeropaieal | in, Pacebo eombiion with ‘Women With onli. tracy | Paens wil wesc iver sndto IAdionced ens | sud fivearamincombinstion eatin te snt = eancer previa lihethe placebo or [tumour actly ofthe ented wih third |AZD3363 uni dieawe | combination of SS progreion Paentsmay | AZD5363 with tee eal fahetots fivearae and messed by AZDsa6%plecebo teatmert_| progres ice ren aertho tat viet [ronal PS) All c.gov studies (NCTO2338531, NCTO1876251, fruit information to the revearchers in the fell of 'NCT02239635) ae terminated due tothe discantinuation oncology especially related to Breast Cancer. The data in ofthe developmentofthe NotchinhibitorPF-02084014,-_ theaticle hasbeen ereved om Conclusion: ‘Breas cancer isthe major concern worlwide amongstthe precareus diseases. nihis sudy we have ied to provide ‘Garrnt Tren in Biotechnology and Cher jsmos popular and ‘most reliable sources lke clinicalrialsgov, Pubmed, ‘pharmaceutical comparies et. Studies included in the aticle are wih completed and ongoing status andar either Breast Cancer Refrences: 1. Lamberini Mt Pago F, Yagica M, Blondkaux E, Del ‘astro L (2016) News on the medical treatment of ‘young women with early-stage HER2-negative breast ‘Cancer Expert OpinPharmacother 1-13. 2. “BreastCancer”.NCI(2016). 3. "Breast cancer". Mayo Foundation for Medical Education and Research (2016) 4. Hal C, Bez K, Schoeneberger Hand Fulda $ (2016) Senstiztion of acute lymphoblast leukemia cll for LCL161-induced cell death by targeting redox homeostasis. Biochem Pharmacol 108:14-22. doi 10.1014jbep.2016.01.004,€oub20161an 13. 5. Tian A, Wilson G'S, Le S, Wu G, Hu Z, Hebbard L, Duan, George] and Qiao L2014)Synerisic flees fof IAP inhibitor LCLI61 and paclitaxel on hepatocellular carcinoma cells. Cancer Le 351(2#232.41. dol: 10.1016)jcanle.2014.06.006, Epub20144n27. 6. Qing, 2u0Y,YangX, Lu], Zhan XUL,-ZhangC,Zho H, Lis | Liv, Tao G, Dai , Zhang X, Ma Cai and Sun X (2018) Smac mimetic compound LCL 6 sentizes etophagea carcinoma cells radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumour Biol 35(3):2565-74. doi 10-10071613277-013-1338-2, 7. Panion M, Badia A, KurmelS, Laura G and Estevez (2015) A phase Il, open-label, neoadjuvant, randomized sudyofUCL16 with pacaxel in patients -withtriple negative breast cancer(TNBO).|Clin Onc 2 8. Friedland JC, Smith L, Sang }, Acquaviva J He S, “Zhang C ard ProiaD A (2014) Tagted inhibition of Hep9D by ganetespib ie effective acrose a broad spectrum of breast cancer subtypes. Invest New Drugs {1 :14-24, doi 10.1007/510637-013-9971-6, 9. ah European Breast Cancer Confrence, in Glasgow, Scotland, oral session (2014) Clin Breas. Cancer 14(35 154-60. doi: 10.1016j.elbe-2013.12012. Epub 201390 28. 10. shaver ChandadapatyS, Lake D,CilewskiT, Rabson 'M, Coldar S,DallnskyP and Sugarman § (2010) A phase Il oper label study of ganetespily, 2 novel heat Shock protein 90 inhibite fr patients ih metasaic breast cancer. Cancer Res 15:70(6:2485.94. doi 10.1158/0008-5472.CAN-09.3145 11 Schocbet B, Faber A C, Li D, Liang MC, Crosby K, ‘Orsum M, Burenkova O, Pace E, Walton Z, Nie L, Falgharn A, Song ¥, Nieken U 8, Engelman | A and 13 14 v, 1. ‘Wong K (2010) An E603 antibody, MM-121,sactive incancerswithligard-dependert activation, Holmes A, Mcntyrek J Krop1E, Osborne CR, Sith 11}, Modisno MR, Gupta M, Downey L8, NandaR, Saleh MN, Young |, Horgan KE, Kubasck W, ‘Macteath G, Dans MA and C’Shaughnessy | A. (2015) A randomized, phase 2 ral of preqperative (MM-I2T with pacltasel in tiple negative (IN) and hormone receptor (HR) postive, HER2-negatve beast ‘cancer ol75, sue 9 Supplement, of Tiry-Seventh ‘Annual CTRCAACR San Antonio Breast Cancer ‘Symposium San Anion, TX Merrimack Pharmaceuticals (2013) MMM-121 Demorsirates Positive Signal in Two Phase 2 ERPRE Breas Cancer Studies, Merimack Prormaceuticals? Merrimack Pharmaceutical’ Therapies Show Promise In Certain Adianced Breas, Casrc And Gynecologic ‘Cancers (2012) Phase 1 Study Results Presented a ESMO 2012 Congress Show E1b83 as Potential “Therapeutic Tage. Fares F, Azzam N, Fares B, Larsen S and Lndkacr- Jensen $ (2014) Benzene-poly-carboxylic acid ‘complex, a novel anti-cancer agent induces apoptosis Inhuman beast cancer ells. PLeS One 912):685156 oi: 10.137 Vjoural pone.0085156.. Lansen 5, uthongkornong k, Manithas A, shina Podkbuskayal, Matrosova M, Seimuninnimit Vand Lindkas-fensen § (2014) BP-CI’in the weatment of patente with sage IV brea cancer: a eandomized, double-blind, placebo-coniolled mulicenter study and an additonal ope-label treatment phase, Breas. Cancer (Dove Med Press) 6:179-89. doi 10.2147/8CTTS71781 Toren Pham$, Kim, AdomatHZoubeid A, Moore W Rand Gleave ME (2014). Anticancer activity ofthe selective CYPITAL inhibitor, VT-464, in preclinical models of casrateresiant prosiate cancer. | Gin ‘Oncol 32(suppl abr 104) \wallin J), Guan Prior WW, Lee LB, Ben, Belmont LD, Koeppen H,Belvn M, Friedman L Sand Sampath 1D 2012) GDC.09a1, a novel class I selective PK initstor enhances the efficacy of docetaxel in human ‘breast cancer models by increasing cel death i vito and in vive. Clin Cancer Res 18(14):3901-11. doi ‘o.115/1078.0432.CCR- 11-2088. Scholiski P,CrosaS, Mayer! A, WersH, Rooney! Apt D, Gendreau 8, MomisseyK, Lacknee M, Spacek} ‘and Winer E (2015), Cancer Researeh, Vol75, le 9, ‘or Thiny-Seversh Annual CTRCAACR San Antonio BreasiCancerSympostum; San Anionio, TX ‘Caret Trens in Biechnoloay and Chemical Reearch, January June 2016] Vol 6 ssi 1 Sharma ea 20, Roche Clinical Wal Regis. 2016) 21, Sarco L, Hidesbiea T, Kung AL, Teng } C Taran D, ‘Yang M, Jape M, van Duzer JH, Maztschek R, Ogier WE. CirsteaD, RadigS Eda ScullenT, Canavese M, Bradner], Anderson KC, Jones § Sand Raje N (2012), Preclinical activity, pharmacodynamic, and pharmacokinetic properties of 2 selective HDACS Inhibitor ACY-1215, in combination with borezomib in multiple myeloma. Blood 119(11:2578-89, doi 10.1162fblod- 2011-10:387365. 22, Davies BR, Greenwood H, Dudley Crater C, YD 1, Zhang} LJ, Gao BQ, Maynard J Rickets SA, ‘Cross D,Coaulch , Chiesa CC, Page K, Yates Lane C, Watson R, Luke R, Ogilvie D and Pass M (2012) Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and ‘conelation of monotherapy activity with genetic “Ther (3873-87, doi 23. Addie M, Ballad P, Butar D, Crater C, Cutie G, Davies BR, Debrcezeni|, Dry H, Dudley, Greenwood R, Johason PD, Kenle IG, Lane C, Lament G, Leach A, Like RW; Moms |, Ogilvie, Page K, Pass, Pearson ‘Sand Ruson (2013) Discovery of -amino-N-(S}-1- (a-ehlorophenyl)-3-hydeoxypropyl]-1-7H- pyrrolo[2,3-dlpyrimidin-4-yi)piperidine-4- ‘carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. | Med Chem '565)2059.75. doi: 10.1021/jn3017624 (Curent Trends in Biotchonlogy aod Chemical Research | January Tune 2016] Ve. 6 [sue 1 E 24, We P, Walls M, Qiu M, DingR, Denlinger RH, Wong, A Tsaparikos Kani] F Hosea, Sands M, Randolph’ and Seeal T (2010) Evaluation of Selective gamma Secretce inhibitor PF-03084014 for ie antitumor ‘etfiaey and gasrointestinal safety to guide opimal

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