Drugs in Clinical Pipeline: GDC-0834 | Treatment of Rheumatoid Arthritis | Antiinflammatory Agent | BTK Inhibitor

GDC-0834 [(R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide] is a potent, selective small molecule inhibitor of Bruton's tyrosine kinase (BTK). Its development followed SAR studies on CGI-1746, another potent and selective BTK inhbitor. GDC-0834 maintained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models.  GDC-0834 inhibits BTK in vitro with an IC₅₀ of 0.006 uM and has an EC₅₀ of 0.060 uM in the cell based CD86 assay. In human whole blood, GDC-0834 demonstrated potent inhibition of both anti-IgE stimulated CD63 expression (basophils) and anti-IgD stimulated CD69 expression (B-cells) with EC₅₀’s of 0.35 and 0.38 uM, respectively [1].

Appreciating its potential for the treatment of rheumatoid arthritis, a single dose IND was filed and GDC-0834 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, GDC-0834 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure.

GDC-0834: 2D and 3D Structure

The activity of GDC-0834 is as follows:

IC₅₀ (BTK enzyme assay) = 0.006 uM

EC₅₀ (Cell Based CD86 assay) = 0.06 uM

Common Name: GDC-0834
Synonyms:  GDC-0834; GDC-0834; GDC 0834
IUPAC Name: (R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
SMILES:O=C(C1=CC(CCCC2)=C2S1)NC3=CC=CC(C(N=C4NC5=CC=C([C@H]6N(C)CCN(C)C6=O)C=C5)=CN(C)C4=O)=C3C
CAS Number: 1133432-46-8
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor
Indication: Anti-Inflammatory Agent; Treatment of Rheumatoid Arthritis
Development Stage: Pre-Clinical
Company: Gilead Pharmaceutical/Genentech

1H NMR (Estimated) for GDC-0834

References:
1. Young, W. B.; et. al. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett 2015, 25(6), 1333-1337 (synthesis and activity).
2. Blomgren, P. A.; et. al. Substituted amides, methods of making, use thereof for the treatment of diseases such as cancer. WO2009039397A2 (synthesis and activity)

Drugs in Clinical Pipeline: GSK2256098 | FAK Inhibitor | Cancer Drug

GSK2256098 [2-[5-Chloro-2-(2-isopropyl-5-methyl-2H-pyrazol-3-yiamino)-pyridin-4-ylamino]-N-methoxy-benzamide] as a potent, selective, reversible, and ATP competitive inhibitor of FAK (Focal adhesion kinase) activity (apparent K_i = 0.4 nM). The cocrystal structure reveals compound bound in the ATP binding pocket of FAK [1].

GSK2256098: 2D and 3D Structure

The potent enzymatic activity translates to cellular activity when  IC₅₀ values for reducing cellular phospho-FAK levels (pFAK-(Tyr 397)) were determined by ELISA. GSK2256098 inhibited cellular pFAK with IC₅₀ values from 2-15 nM and level of pFAK remained low over time in the continues presence of the compound [1].

1H NMR (Estimated) for GSK2256098

References:

1. Auger, K. R. et. al. The Focal Adhesion Kinase Inhibitor GSK2256098: a Potent and Selective Inhibitor for the Treatment of Cancer. Eur J Cancer 2012, 48, 118.

Drugs in Clinical Pipeline: Pacritinib | Dual Kinase Inhibitor | JAK2 Inhibitor | FLT3 Inhibitor

Pacritinib [11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene] is a novel low-molecular weight pyrimidine-based macrocycle with potent inhibitory activities against Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3). 

Pacritinib shows a unique kinase profile with selective inhibition of Janus Kinase-2 with IC₅₀ values of 23 and 19 nM against JAK2^WT and JAK2^V617F respectively and an IC₅₀ value of 22 nM gainst FLT3. Within the JAK family, Pacritinib has IC₅₀ values of 50, 520 and 1280 nM for TYK, JAK3 and JAK2, respectively, showing high preference for JAK2. The rest of the evaluated kinases showed less than 30% inhibition when tested against 100 nM Pacritinib at ATP concentrations equivalent to its Michaelis constant (K_m) [1].

Pacritinib: 2D and 3D Structure

The activity of Pacritinib is as follows:

IC₅₀ (JAK1 enzyme assay) = 1280 ± 370 nM
IC₅₀ (JAK2 enzyme assay) = 23 ± 6 nM
IC₅₀ (JAK2^V617F enzyme assay) = 19 nM
IC₅₀ (JAK3 enzyme assay) = 520 ± 110 nM
IC₅₀ (TYK2 enzyme assay) = 50 ± 6 nM
IC₅₀ (FLT3 enzyme assay) = 22 ± 6 nM
IC₅₀ (FLT3^D835Y enzyme assay) = 6 nM

1H NMR (Estimated) for Pacritinib

References:

1. Hart, S.; et. al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 2011, 25(11), 1751-1759.

Drugs in Clinical Pipeline: AZD1480

AZD1480 [(S)-5-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine] is an oral, potent, ATP competitive, small molecule inhibitor of Janus Kinase 2 (JAK2) kinase, with an inhibition constant (K_i) of 0.26 nM. 

To evaluate Jak family selectivity of AZD1480, enzymatic assays were carried out Jak1, Jak2, and Jak3  at K_m levels of ATP and 5 mM ATP, which is the high end of ATP concentrations in cells. AZD1480 demonstrated significant Jak2 selectivity over Jak3, in particular at high ATP concentrations and marginal selectivity over Jak1 at K_m ATP [1].

The activity of AZD1480 is as follows:

IC₅₀ (JAK1 enzyme assay, K_m ATP) = 1.3 ± 0.1 nM

IC₅₀ (JAK2 enzyme assay, K_m ATP) = less than 0.4 nM

IC₅₀ (JAK3 enzyme assay, K_m ATP) = 3.9 ± 0.7 nM

IC₅₀ (JAK1 enzyme assay, 5 mM ATP) = 41 ± 1.0 nM

IC₅₀ (JAK2 enzyme assay, 5 mM ATP) = 58 ± 2.4 nM

IC₅₀ (JAK3 enzyme assay, 5 mM ATP) = 1363 ± 113 nM

References:

1. Zinda, M.; et. al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009, 16(6), 487-497. 

Momelotinib | JAK1, JAK2 Inhibitor | Janus Kinase Inhibitor | Therapy for Myelofibrosis

Momelotinib [N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide] is a small-molecule, ATP-competitive and highly selective inhibitor for Janus Kinase 1 (JAK1, IC₅₀ = 11 nM) and Janus Kinase 2 (JAK2, IC₅₀ = 18 nM). Momelotinib inhibited JAK1 and JAK2 equipotently, but had an IC₅₀ that was approximately ninefold higher for the closely related JAK3 (IC₅₀ = 155 nM) kinase as compared with JAK2.

Momelotinib: 2D and 3D Structure

In a ‘single-point’ screening assay that assesses the degree of enzyme inhibition at a specified Momelotinib concentration (100 nM or 1 uM), only eight kinases (JAK1, JAK2, CDK2/A, ROCK2, MAPK8, TBK1, PRKD1 and PRKCN) showed less than 50% at 100 nM [1].

Summary

Common name: CYT387; CYT 387; CYT-387; CYT 11387; CYT-11387; CYT11387

Trademarks:

Molecular Formula: C23H22N6O2

CAS Registry Number: 1056634-68-4

CAS Name: N-(Cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide

Molecular Weight: 414.47

SMILES:O=C(NCC#N)C1=CC=C(C2=NC(NC3=CC=C(N4CCOCC4)C=C3)=NC=C2)C=C1

InChI Key: ZVHNDZWQTBEVRY-UHFFFAOYSA-N

InChI: InChI=1S/C23H22N6O2/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)

Activity: Treatment of myelofibrosis; Anti-neoplastics Drug; Anti-inflammatory Agents

Status: Phase I/II

Originator: Gilead Sciences

Momelotinib Synthesis

US8486941B2: This is first disclosed synthesis for Momelotinib. It doesn't appear to be industrially optimized.

WO2015191846: The scheme is derived from the patent.

Identifications:

1H NMR (Estimated) for Momelotinib

13C NMR (Estimated) for Momelotinib

Experimental: ¹³C NMR (75.5 MHz, d₆-DMSO) δ 166.04, 162.34, 160.26, 159.14, 146.14, 139.87, 134.44, 132.73, 127.80, 126.84, 120.29, 117.49, 115.50, 107.51, 66.06, 49.16, 27.68.

References:
1. Pardanani, A.; et. al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 2009, 23(8), 1441-1445.
2. Brown, B. H.; et. al. N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts. WO2015191846A1

3. Burns, C. J.; et. al. Phenyl amino pyrimidine compounds and uses thereof. US8486941B2

Drugs in Clinical Pipeline: Apitolisib

Apitolisib [(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one] is a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase (PI3K) and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. Apitolisib displayed excellent potency against class I PI3K isoforms (IC₅₀ PI3K-α, β, δ and γ = 4.8, 27, 6.7 and 14 nM) and mTOR kinase (IC₅₀ = 17 nM) and selectivity against a large panel of other kinases, including closely related PIKK family members DNA-PK (K_i = 623 nM), VPS34 (IC₅₀ = 2000 nM), c2alpha (IC₅₀ = 1300 nM), and c2beta (IC₅₀ = 794 nM) [1, 2].

References:
1. Sutherlin, D. P.; et. al. 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. J Med Chem 2011, 54(21), 7579-7587.
2. Wallin, J. J.; et. al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011, 10(12), 2426-2436.

Drugs in Clinical Pipeline: RO-9021

RO-9021 [(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide] is an oral, ATP-competative and selective inhibitor of spleen tyrosine kinase (SYK). RO-9021 potently inhibited SYK kinase activity with an average IC₅₀ of 5.6 nM. Selectivity of RO-9021 against a panel of 451 wild-type and mutant protein kinases was assessed using an ATP binding site competition assay developed by KINOMEscan Inc.  

RO-9021 is a highly selective SYK inhibitor with low S-scores of 0.003 for S(99) and 0.015 for S(90), indicating that SYK is the only kinase with 99% competition with RO-9021 (1 uM) in a total of 392 tested kinases. There were only a total of seven kinases (JAK1, JAK3, GCN2, SLK, FLT3(ITD), PAK2) including SYK, having more than 90% competition with RO9021. It inhibited JAK1 and JAK3 with 97% at 1 uM.

References:

1. Liao, C.; et. al. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy. Arthritis Res Ther 2013, 15(5), R146.

Drugs in Clinical Pipeline: GSK143

GSK143 [2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide] is a potent and highly selective spleen tyrosine kinase (SYK) inhibitor (pIC₅₀ = 7.5) showing good efficacy in the rat Arthus model. The selectivity profile of GSK143 was determined against a panel of 66 protein kinases and none were inhibited within 10-fold of SYK activity. GSK143 is greater than 600-fold selective for SYK over ZAP-70 (pIC₅₀ = 4.7), the other member of the SYK kinase family [1].

The activity of GSK143 is as follows:

pIC₅₀(SYK enzyme assay) = 7.5

pIC₅₀(ZAP-70 enzyme assay) = 4.7

pIC₅₀(LCK enzyme assay) = 5.3

pIC₅₀(LYN enzyme assay) = 5.4

pIC₅₀(JAK1 enzyme assay) = 5.8

pIC₅₀(JAK2 enzyme assay) = 5.8

pIC₅₀(JAK3 enzyme assay) = 5.7

pIC₅₀(AURKB enzyme assay) = 4.8

Common Name: GSK143

Synonyms: GSK143; GSK-143; GSK 143

IUPAC Name: 

CAS Number: 1240390-27-5

SMILES:

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor; Spleen Kinase Inhibitor

Indication: Various Cancers; Anti-inflammatory Drugs

Development Stage: Investigational

Company: GlaxoSmithKline

The progression of GSK143 was terminated due to a mutagenicity risk highlighted in the Ames assay, it remains one of the most selective SYK inhibitors disclosed to date and hence an excellent tool molecule for further evaluation of the SYK mechanism.

References:
1. Liddle, J.; et. al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett 2011, 21(20), 6188-6194.

Drugs in Clinical Pipeline: GSK-1614235

GSK-1614235 [3-{[3-(4-{[3-(ß-D-Glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-yl]methyl}-3-methylphenoxy)propyl]amino}-2,2-dimethylpropanamide] is a potent and selective inhibitor of SGLT1. It has inhibition constant (K_i) values of 27 and 8170 nM for human (h) SGLT1 and hSGLT2, respectively. GSK-1614235 is an analog of KGA-2727 and has nearly 2 fold more specificity for SGLT1 than KGA-2727. Also, this specific behaviour towards SGLT1 makes GSK-1614235 an unique inhibitor compared with other molecules that primarily inhibit renal glucose reabsorption via SGLT2 or have dual effects on SGLT1 and SGLT2 [1].

References:
1. Dobbins, R. L.; et. al. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol 2015, 308(11), G946-G954.
2. Fushimi, N.; et. al. Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof. US20090203633A1 (synthesis and activity)

Drugs in Clinical Pipeline: KGA-2727

KGA-2727 [3-(3-{4-[3-(beta-D-glucopyranosyloxy)-5-isopropyl-1Hpyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide], is the first reported selective SGLT1 inhibitor which has a pyrazole-O-glucoside structure. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. It has inhibition constant (K_i) values of 97 and 13,600 nM for human (h) SGLT1 and hSGLT2, respectively.

In March 2005, Kissei Pharmaceutical Co., Ltd. and Dainippon Pharmaceutical Co., Ltd. announced that they have entered into a license agreement on "KGA-2727", a novel agent for the treatment of diabetes, which was discovered by Kissei. It was reported than in future, Kissei will continue to conduct non-clinical studies while Dainippon will conduct clinical development and marketing in Japan. Kissei reserves the right to participate in the clinical development to be conducted by Dainippon as well as the right to co-market the agent. Kissei continues to own the right for this agent outside Japan, including the right for development, manufacturing and marketing.

Drugs in Clinical Pipeline: SHR3824

SHR3824 [(1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol] is a novel, oral and selective SGLT2 inhibitor, which is structurally different from other SGLT2 inhibitors (flozins) that are currently available or in the late stages of clinical development.

In vitro, SHR3824 potently inhibits human SGLT2, but exerts much weak inhibition on human SGLT1 (IC₅₀ hSGLT2, hSGLT1 = 2.38 and 4324 nM, respectively) showing a selectivity of 1817 for SGLT2. Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg.d) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice [1].

SHR3824 is discovered by Shanghai Hengrui Pharmaceuticals Co, Ltd, (Shanghai) and is currently in Phase I clinical studies in China  for treatment of type 2 diabetes (T2DM).

References:
1. Yan, P. K.; et. al. SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models. Acta Pharmacol Sin 2014, 35(5), 613-624.

Drugs in Clinical Pipeline: LIK066

LIK066 [(2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, (S)-Pyrrolidine-2-carboxylic acid (2:1)] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 22.0 nM against human SGLT1 and 0.5 nM against human SGLT2 [1, 2].

References:

1. Opinion of the Paediatric Committee on the agreement of a Paediatric Investigation Plan and a deferral and a waiver. 2014, EMEA-001527-PIP01-13 (here) [ Novartis revealed the IUPAC name here].

2. Bebernitz, G. R. Glycoside derivatives and their uses for the treatment of diabetes. WO2012140597A1 (synthesis and activity)

Drugs in Clinical Pipeline: Sotagliflozin

Sotagliflozin [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 36 nM against human SGLT1 and 1.8 nM against human SGLT2.

Drugs in Clinical Pipeline: Vistusertib | mTOR Inhibitors | Kinase Inhibitors

Vistusertib [3-[2,4-Bis((3S)-3-methylmorpholin-4-yl)pyrido[5,6-e]pyrimidin-7-yl]-N-methylbenzamide] is an oral, potent and selective dual mTORC1/mTORC2 inhibitor with clear activity in in vivo and in vitro experimental models. It is under clinical trials against various cancers as monotherapy as well in combination with other anti-cancer agents such as Estrogen Receptor Positive (ER+) Metastatic Breast Cancer, Metastatic Renal Cancer, Glioblastoma Multiforme, Ovarian Cancer etc [1, 2].

Vistusertib: 2D and 3D Structure

mTOR as Target for Cancer Treatment

Growth factor/mitogenic activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway ultimately leads to the key cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin associated protein), RAFTl (rapamycin and FKBP12 target 1), RAPTl (rapamycin target 1) - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)) [3]. 

mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases. The mTOR protein is a member of the PB-kinase like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PI3-kinase and the other family members, e.g. DNA-PKcs (DNA dependent protein kinase), ATM (Ataxia- telangiectasia mutated).

PI3K-Akt-mTOR pathway is one of the most frequently dysregulated pathways in cancer. The mammalian target of rapamycin (mTOR) is a key target in the development of antitumor therapies. The finding that mTOR can exist in an alternative, rapamycin insensitive, complex that signals to Akt opened up a new line of thinking for the researchers. The existence of both a rapamycin sensitive complex (mTORC1) and a rapamycin insensitive complex (mTORC2) may provide an explanation for the differences observed in the earlier research works. Rapamycin and its analogues have been shown to activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1. Moreover, this is associated with a shorter time to progression in glioblastoma patients treated with rapamycin suggesting that dual mTORC1 and 2 inhibitors that inhibit AKT signaling could offer greater clinical benefit compared with rapalogues. In addition, dual mTORC1 and mTORC2 inhibitors may exhibit a broader spectrum of clinical activity [2].

 Vistusertib as mTOR Inhibitor

Vistusertib is a potent inhibitor of mammalian target of rapamycin (mTOR) kinase (IC₅₀ = 0.0028 uM) and displays a high level of selectivity against other members of the PIKK family (IC₅₀ PI3Kα = 3.8 uM, PI3Kβ, γ, δ greater than 29 uM, respectively). It was inactive against a general panel of over 200 kinases when tested at 10 uM. In in vivo studies, Vistusertib has been shown to modulate downstream markers of mTORC1 (inhibition of pS6 at Ser235/236 IC₅₀ = 0.2 uM) and mTORC2 (inhibition of pAKT at Ser473 IC₅₀ = 0.08 uM). Moreover, it has shown dose-dependent tumor growth inhibition in a mouse MCF7 xenograft model alongside modulation of mTORC1 and mTORC2 biomarkers.

Vistusertib showed excellent aqueous solubility (more than 600 uM), margin to the hERG (IC₅₀ = 47.5 uM) and was shown to have good oral exposure in both rat (100%) and mouse (40%). Vistusertib shows consistent exposure in rodents and a low turnover in human hepatocyte incubations and was subsequently selected for clinical development. Vistusertib is currently in Phase I/II [1, 2].

Dosages and Approvals:

Vistusertib (Tradename: -) is discovered and developed by Kudos Pharmaceuticals, later aquired by AstraZeneca. It is still under clinical trials.

Reported Activities for Vistusertib

IC₅₀ (mTOR enzyme assay) = 2.8 nM

IC₅₀ (PI3Kα enzyme assay) = 3.8 uM

IC₅₀ (PI3Kβ enzyme assay) = greater than 30 uM

IC₅₀ (PI3Kγ enzyme assay) = greater than 30 uM 

IC₅₀ (PI3Kδ enzyme assay) = greater than 29 uM

Summary

Common name: AZD2014; AZD-2014; AZD 2014; Vistusertib

Trademarks: -

Molecular Formula: C25H30N6O3

CAS Registry Number: 1009298-59-2

CAS Name: 3-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide

Molecular Weight: 462.54

SMILES:C[C@@H](COCC1)N1C2=NC(N3[C@@H](C)COCC3)=NC4=NC(C5=CC(C(NC)=O)=CC=C5)=CC=C42

InChI Key: JUSFANSTBFGBAF-IRXDYDNUSA-N

InChI: InChI=1S/C25H30N6O3/c1-16-14-33-11-9-30(16)23-20-7-8-21(18-5-4-6-19(13-18)24(32)26-3)27-22(20)28-25(29-23)31-10-12-34-15-17(31)2/h4-8,13,16-17H,9-12,14-15H2,1-3H3,(H,26,32)/t16-,17-/m0/s1

Mechanism of Action: Kinase Inhibitors; Dual mTOR Inhibitor

Activity: Various Cancers; Treatment for Breast Cancer; Anti-Cancer Agents

Status: Phase Trials (US)

Chemical Class: Small-molecules; Benzamides; Morpholines; Pyridines; Pyrimidines

Originator: AstraZeneca

Vistusertib Synthesis

WO2008023161A1: It is the oldest reported synthetic procedure for preparing quantitative amounts of Vistusertib and derivatives. The process involves sequential addition of 3S-Methylmorpholine at C4 and C2 position of trichloro intermediate, followed by using suitable boronic acid (or esters) via palladium mediated cross couplings to generate compounds. See also Ref 2.

Identifications:

1H NMR (Estimated) for Vistusertib

Sideeffects: The adverse events (AEs) were gastrointestinal symptoms such as nausea, mucositis, diarrhea and vomiting in 21/41 (51%), 20/41 (49%) 17/41 (42%), and 12/41 (29%) as reported by participants. However, less than 5% of these adverse events were grade 3 or 4. Nausea and vomiting were well controlled by antiemetics, such as domperidone, if necessary, and the grade 1-2 diarrhea did not consistently require treatment. Mucositis was grade 1-2 in most instances and patients responded to mouth-washes and did not require dose interruptions due to it. A predominantly maculopapular rash was observed in 17/41 (42%) of patients and less than 5% of these were grade 3 or higher. Lower respiratory tract infections were seen in 7/41 (17%) and it was grade 3 in only 1/41 (2%). Interestingly, no patients were diagnosed with pneumonitis.

The most common laboratory abnormality was anemia, with 7/41 (17%) having recorded grade 1-2 anemia; given the advanced cancer and degrees of co-morbidities in these patients, it was difficult to attribute this specifically to AZD2014. Hyperglycemia was seen in 5/41 (12%), 0/5 (0%), and 2/4 (50%) of patients treated at 50 mg BD, 70 mg BD and 100 mg BD, respectively [4].

Others: Readers can suggest.

References:

1. Guichard, S. M.; et. al. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules. Mol Cancer Ther 2015, 14(11), 2508-2518. (free article)

2. Pike, K. G.; et. al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett 2013, 23(5), 1212-1216. (FMO only)

3. Duggan, H. M. E.; et. al. 2-methylmorpholine pyrido-, pyrazo- and pyrimido-pyrimidine derivatives as mtor inhibitors. WO2008023161A1

4. Basu, B.; et. al. First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. Clin Cancer Res 2015, 21(15), 3412-3419. (free article)

1 2 3