11,l4 cX5'æ-/ A/.-l t..!: ~¿ -4, ,t'l.Á/, · Module 2, Page 2 Name 10 Number ... nuclear...

11,l4 cX5'æ-/ A/.-l t..!: ~¿ -4, ,t'l.Á/,Phar 754 S2007 (Stevens/Leid) ,J,Jpff "e ~ ~~~ -Aels ,Module 2, ~age 1 10 Number - ;...~

t,/ ZJ'l'" lJ l~ ".."\ .." ('!""- .é"': ,/ '. "l_ ¡ijt~~,~' \ ii/t/ t 'C)(~¡t t'ßC l c cR

, lease read each questio~ very carefully and record your answer on thescantron. You have until 2:50 p.m. to complete the exam.

1. C-The DNA binding domaiQ (OBO) of nuclear receptors...,

B.C.-A. Is responsible for the binding of hormones or Iigands by receptors with

known hormones or Iigands "Is responsible for the binding of hormone or ligand by orphan receptorsIs the primary determinant of the specificity with which nuclear receptorsbind directly to a target gene promoter

O. Is the primary determinant of the specificity with which nuclear receptorsbind directly to transcriptional corepressor complexes

E. Is the primary determinant of the specificity with which nuclear receptors

bind directly to transcriptional coactivator complexes

2.L The ligand (or hormone) binding domain (LOB) of nuclear receptors...

~11.

Is responsible for the binding of Iigands or hormones byreceptors with known hormones or IigandsInteracts directly' with transcriptional corepressor complexesin a manner that is inhibited by agonist ligands or hormonesInteracts directly with transcriptional coactivator complexesin a manner that is stimulated by agonist ligands orhormones

II i.

(Â i onlyB. '" onlyC. i and II onlyO. II and ILL only

E. i, ", and '"

3.)\ Activated (agoni,st-bou~d) nuclear receptors directly influenæ...

/A The rate of formation ,of the ",!anscriptional pre-initiation complex~ containing RNA polymerase II f;c

Z. The extent of phosphorylation of the C-terminal domain of RNA

polymerase II,.e: The rate of RNA polymerization by RNA polymerase II

/13 The termination of RNA polymerization by RNA polymerase II"E. The processing of nuclear RNA synthesized by RNA polymerase II into

mature RNA

Phar 754 S2007 (Stevens/Leid)Module 2,

Name10 Number

4.LwhiCh of the following most likely underlies the mechanism for youranswer in the previous question (question #3)?

r( Activated nuclear receptors recruit a series of enzymes to the promotertemplate, and these enzymes covalently mortify histones, resulting in anenvironment that is permissive for transcriJ?tional activation

/9: Nuclear receptors harbor intrinsic kinase activity th-ãC selectivelyphosphorylates the C terminal domain of RNA polymerase IINuclear receptors deliver, nucleosides to the active site of RNApolymerase IiNuclear reæptors are anti-termination factors for RNA polymerase IINuclear receptors recruit splicing factors to the template, resulting in thecovalent modification and enhanced activity of these factors

/:ø/~ 5.LWhat is the general role of heat shock proteins (HSPs) in steroid hormone

receptor signaling?

HSPs deliver the hormone to the appropriate receptorHSPs hold the reæptor in a conformation that is competent to bindhormoneHSPs hold the receptor in a conformation that is competent to bind DNAin a sequenæ-specific mannerHSPs harbor intrinsic histone deacetylase (HOAC) activity that underliessteroid hormone reæptor-mediated transcriptional repressionHSPs harbor intrinsic histone acetyltransferase (HAT) activity thatunderlies steroid hormone receptor-mediated transcriptional activation

,?r~"' :?~6. C-What is the general role of nuclear receptor corepressor' (NCoRì in C'/J~AJ c.

nuclear receptor signaling? ' c"c",.ß~t-..l-i_

, A.B.--ø.

ÁÆ.

D.

lZ

C.

NCoR is a histone deacetylase (HOAC) that is implicated in nuclearreceptor-mediated transcriptional repression.NCoR is a histone methyltransferase (HMT) that is implicated in nuclearreceptor-mediated transcriptional repression.NCoR serves as an adaptor protein that interacts with both unligandednuclear receptors and HOACs, and is implicated in transcriptionalrepression mediated by some types of apo-nuclear reæptorsNCoR serves as an adaptor protein that interacts with both' unligandednuclear receptors and HMTs.NCoR is a component of the 26S proteosome complex that isresponsible for degradation of the nuclear receptors in the context of

transcriptional activation

O.

E.


Name10 Number

7.-t The binding of CWdogelJQUS hormones or agonist drugs to nuclear

receptors generally...

~B.

,

/i i.

Promotes a conformation of the reæptor that is competent tointeract with the corepressor complexPromotes a conformation of the reæptor that is competent tointeract with proteins containing a LXXLL motif, where L =leucine and X represents any am'ino acid

Promotes a conformation of the reæptor that is competent tointeract with the coactivator comolex

II i.--i only'" onlyI and II onlyII and '" onlyi, ", and '"

;;8.-UBeavo-1, a protein containing a bromo domain, is a key component of the

RNA polymerase II transcriptional compleX. Beavo-1 does not interactdirectly with estrogen reæptor a (l but yet Beavo-1 was shown to berecruited to the promoter template of an ERa target gene in an .estradiol-dependent mann~r. Which of the following most likely precedes therecruitment of Beavo-1,to this promoter template?

)4

¿~

A. Monomethylation of arginine in the context of histone H3 by a protein, arginine methyltransferaseSymmetrical dimethylation of arginine in the context of histone H4 by aprotein arginine methyltransferaseMonomethylation of lysine in the context of histone H3 by a histonemethyltransferaseMonomethylation of lysine in the context of histone H3 by a histonemethyltransferaseAcetylation of lysine in the context of histone H3 by steroid receptorcoactivator 1 (SRC1)

B.


Name10 Number

9.ZranscriPtional activaln mediated by ERa is a multi-step process thatinèludes the cvclical recruitment of many enzymatic activities to thetemplate in an estradiol- and ERa-dependent manner. Histonedeacetylases (HOACs) represent one class of histone-modifying activitiesthat are recruited to the promoter template of ERa target genes. What isthe most likely role of HOACs in this context?

/~&)/.

HDACs create an environment that is necessary for the appearance ofRNA polymerase Ii on the templateHOACs playa key role in promoter clearance by RNA polymerase IIHOACs playa key role in elongation by RNA polymerase IIHDACs reset the basal state' of acetylation of promoter-associatedhistonesHOACs playa role in receptor degradation

10. CAhe tissue-specific activity of selective estrogen receptor modulators(SERMs) has puzzled many clinicians for a number of years. Which of thefollowing most likely underlies the agonist- and antagonist-like activities oftamoxifen in uterus and breast, respectively?-- k,(I"'' Æ~r-

A. The relative expression levels of ERa in these two tissuesB. The relative expression levels of ERß in these two tissues

~. The relative expression levels of SRC1 in these two tissues'ß The relative expression levels of Cyp3A4 in these two tissuesE. The relative expression levels of Cyp2B 10 in these two tissues

11. ~he tissue in which the pharmacological actions of raloxifene and/t~moxifen differ most obviously is:

A.

~O.E.

BreastUterusBoneVascular systemCentral nervous system


Name10 Number

12.c. certain contexts, DNA binding is not required in order for glucocorticoidreceptor (GR) to exert regulatory control over gene expression. Howmight GR regulate transcription of certain target genes in the absence ofdirect:LA binding activity?

A.

B.

By inducing metabolism of Iigands/hormones that activate otherreceptorsBy inhibiting metabolism of Iigands/hormones that activate otherreceptorsActivated GR can be localized to the promoter region and serve as atranscriptional regulatory protein by tethering to other promoter-boundtranscription factors ~By interacting with heat shock protein(s) in the cytoplasmGR must be bound directly to DNA to exert transcriptional regulatoryactivity

ß)p:,.

13. ~WhiCh of the following is/are a direct, target gene(s) of PPARy inmacrophages?

i. ¡, C036, the receptor for oxidized LOL-cholesterol

11. Liver X Receptor a (LXRa)

II.~ ATP-Binding Cassette A1 (ABCA1)

~t

i onlyII onlyi and II onlyII and '" onlyi, ", and ill

14.1LAn agonist of LXRa may be useful in the treatment of..--A. Elevated LDL-cholesterollevels

B. Elevated HOL-cholesterollevels

C. HypertriglyceridemiaO. Type 2 diabetesE. Obesity


Name10 Number

15. 0he most likely adverse effect associated with the LXRa agonist in theprevious question may be...

A. Elevated LOL-cholesterollevels

B. Elevated HOL-cholesterollevels

C. Hypertriglyceridemia

)r Type 2 diabetes~ Obesity

16. Cwhich of the following is a direct agonist o!.LXRa? c.~ S / ~~e: /

Kl43?

GemfibrozilPioglitazone22(R)-hydroxycholesterolGuggulsterone / J JChenodeoxycholic Acid ¡51é' jfl"/(b 4~~/b

17..!Which of the following is a direct agonist of farnesoid X retptor (FXR)?

A.B.C.

&

GemfibrozilPioglitazone22(R)-hydroxycholesterolGuggulsteroneChenodeoxycholic Acid

18£WhiCh of the following is an antagonist offarnesoid X receptor (FXR)?

A.B.

~

GemfibrozilPioglitazone22(R)-hydroxycholesterolGuggulsteroneChenodeoxycholic Acid

Phar 754 S2007 (Stevens/Leid) NameModule 2, 10 Number

19. ~ What is the rationale for the use of gem~: a type 2 diabetic?

A.

B.

C.

o.

~

Gemfibrozil acts as an insulin sensitizer and improves glucosehomeostasis 'Gemfibrozil induces insulin secretion and improves glucosehomeostasisGemfibrozil blocks glucose uptake from the gut and improvesglucose homeostasisGemfibrozil inhibits gluconeogenesis in liver and improves glucosehomeostasisGemfibrozil is used to treat hypertriglyceridemia in the type 2

diabetici

20,fJ What is the rationale for the use of Pi.f:i~'in a type 2 diabetic?

(0B.

C.

o.

E.

Pioglitazone acts as an insulin sensitizer and improves glucosehomeostasisPioglitazone induces insulin secretion and improves glucosehomeostasisPioglitazone blocks glucose uptake from the gut and improvesglucose homeostasisPioglitazone inhibits gluconeogenesis in liver and improves glucosehomeostasisPioglitazone is used to treat hypertriglyteridemia in the type 2diabetic

21. ~t least one component of the medicinal herb St John's wort (Hypericum

perforatum) is an of the nuclear receptorand this results in

Aß~o./

Agonist, Retinoid X Receptor a (RXRa), hyperglycemiaAgonist, PPARa, hypertriglyceridemiaAgonist, Steroid X -Receptor (SXR), induction of Çyp3A4Antagonist, Steroid X Receptor (SXR), inhibition of Cyp3A4Antagonist, LRH-1, enhanced bile acid biosynthesis


Name10 Number

22. e What would likely be the most prominent adverse effect associated withadministration of a long-acting GnRH receptor agonist to a pre-menopausal patient suffering from mòderate to severe endometriosis?

A. Polycystic ovary disease

A Severe pelvic pain that is associated with endometriosisX Hot flashesO. Paget's disease-0 Virilzation

2~A rare but lethal consequence that has been reported in patientsundergoing medical abortions (Le., given mifepristone + misoprostol) is...-- F~(!/O.E.

Toxic shock associated with a concomitant Staphylococcus aureusinfectionToxic shock associated with a concomitant Clostridium sordelliinfectionToxic shock associated with a concomitant Helicobacter pyloriinfectionToxic shock associated with concomitant osteonecrosisToxic shock associated with concomitant ectopic (tubal) pregnancy

24. k Which of the following most likely underlies the therapetic usefulness ofvorinostat (also known as SAHA,; 7J~OJ¡If\ TM) in the treatment of

cutaneous T cell lymphoma? r NSl/ 1Nt.Jvi I1lJìtC,o

(i Inhibition of histone deacetylases (HOACs), resulting in theinduction of apoptosis selectively in transformed (malignant) cellsB. Stimulation of HOACs, resulting in the induction of apoptosis

selectively in transformed (malignant) cells.C. Activation of RXRa in the lesion, resulting in the induction of

apoptosis selectively in transformed (malignant) cellsO. Inhibition of DNA methyltransferase(s) in the lesion, resulting in the

induction of apoptosis selectively in transformed (malignant) cellsE. Inhibition of Protein Arginine Methyltransferases(s) in the lesion,

resulting in the induction of apoptosis selectively in transformed(malignant) cells

Phar 754 S2007 (StevenslLeid)Module 2,

Name10 Number

25. Pcutaneous T cell lymphoma cells expressing andwould be the least sensitive to vorinostat-induced

apoptosis.

A. FLlCE, BidB. FLlcE, FLIPC. FLlCE, Decoy receptor 1 (DcR1)

CQ FLIP, OcR1E. caspase 8, Caspase 3

Questions 26-30 are ~o one (1) point each. Please match the choices formechanism of action -E ith the appropriate agent used ,in the treatment ofost~,or~sis. Please no e that some agents can work v¡'a multiple mechanisms

of ac Jon, depending on the dosing routine, etc. In this case, select only .Q

choice on your scantron and you wil receive full credit (assuming thatyou've selected one of the correct mechanisms for that agent).

P26. Vitamin 0 A. Stimulation of osteoblast activity

¿27. Calcitonin B. Inhibition of osteoclast activity

lLi:. T eriparatide

-r29. Alendronate

A 30. Raloxifene

C. Increased renal excretion of Ca++

D. Stimulation of Ca++ absorption from gut

E. Stimulation of osteoclast activity

Phar 754 S2007 (Stevens/Leid) NameModule 2, 10 Number

31. VThe compound shown below is gl~'iát. a saonin found in theroots of Glycyrrhiza glabra. It is a component of licorice. (3 pts)

H~,\ _1"HO;;~~~HO H

HOHO 0HOO

hll,L //~.s.z

Glycyrrhizic acid causes hypertension through...

A. Agonism of the glucocorticoid receptor.B. Agonism of the mineralocorticoid receptor.

t! Inhibition of 11 ß-HS02, which primarily leads to enhanced levels ofcortisol.O. Inhibition of 11 ß-HSD2, which primarily leads to enhanced levels of

aldosterone.E. Intenerence with the hemi-acetalization of aldosterone, which leads to

enhanced levels of 'free' aldosterone.

32. ? The steroid shown below is a biosynthetic precursor of thecorticosteroids. Which enzyme is most certainly NOT involved in thepathway leading to the corticosteroids? (3 pts)-

(,1

A. 3ß-HSO.B. 11 ß-hydroxylase.

C. 21 ß-hydroxylase.

Æ:ì ,20-lyase.~ 17a-hydroxylase.


Name10 Number

33.-é Which statement regarding the anti-inflammatory drug shown below isincorrect? (3 pts)

o ¡CIo"6;~~

A. Ester hydrolysis of the 17a-substituent sets the stage for the formation

of a 17a-hydroxy group.B. Ester hydrolysis of the 17a-substituent gives an instable carbonic acid

mono-ester.C. Ester hydrolysis of the 17ß-substituent gives an inactive carboxylate.

O. Oxidation of the 11 ß-hydroxy group renders the compound inactive.E. It is a prod rug and is activated through ester hydrolysis after systemic

absorption.

34. ? The immediate biosynthetic precursor of compoun.9s... (3 pts)

-r'/..~,/,/ A

.l/'.J/'

~/j

OH

A. Compound B.B. Compound C.C. Compound O.

(e Compound E.E. Compound F.


Name10 Number

35.Â- The most potent anti-inflammatory steroid for use in dermatologicalpreparations is...(3 pts)

,,10

OH

o

a:ompound A.B. Compound B.,C. Compound C.O. Compound O.E. Compound E.

OH

36. V The steroid drug shown below is a... (3 pts)

CHa

A. Mineralocorticoid.

B. Glucocorticoid.

(§ Progesterone derivative.O. Progestin.E. Prednisolone metabolite.

Phar 754 S2007(Stevens/Leid)Module 2,

NameID Number

37. GWhiCh one of the following compounds is the presumed activecomponent of MENOHop? (3 pts)

OH

OH 0

HO

Pß OH

HO H

HO

~

A. Compound A.B. Compound B.

(QCompound C.'i Compound O.

E. Compound E.

38.~ Which one of the following statements regarding the compound shown

below is correct? (3 pts)

~ ~:!~ ~o ,( rti/""'ú Dif'

OH

HOA. It is a SERM and therapeutically used for treatment of early and

advanced breast cancer in post-menopausal women.jt It is a SERM and has found extensive use in hormone replacement

/ therapy.C. It is an estrogen receptor antagonist.13 It is aSERM and therapeutically used for prevention and treatment of

osteoporosis in postmenopausal women.E. It is a SERM and therapeutically used for treatment of endometriosis.

Phar 754 82007 (Stevens/Leid)Module 2,

Name10 Number

39. A- The compound shown below is a(n)... (3 pts)

êYOrally active androgen. '~ Orally active glucocorticoid.

a Progestin.~ Anti-androgen through inhibition of 5a-reductase.

r Anti-androgen through antagonism of the androgen receptor.

40. C/ The compound shown below is a(n)...(3 pts)

orNHgN~

02N l.ó 0CFa

A. Aromatase inhibitor through binding to the heme group of the CYPenzyme.

B. Aromatase inhibitor through covalently binding to the CYP enzyme.lC-lnti-androgen by antagonizing the androgen receptor.

'- Anti-androgen through covalently binding to the androgen receptor.

E. Anti-androgen through covalently binding to a co-factor of 5a-reductase.


Name10 Number

41.K The compound shown below is a(n)...(3 pts)

0(5 t2/u/~ k¡U~~s~NHk

A. Aromatase inhibitor through binding to the heme group of the CYPenzyme.

S. Aromatase inhibitor through covalently binding to the CYP enzyme.C. Anti-androgen by antagonizing the androgen receptor.O. Anti-androgen through covalently binding to the androgen receptor.

~nti-androgen through covalently binding to a co-factor of 50-~eductase.

42. ~he compound shown below is a(n)...(3 pts)

"11== H

Gl(~cc:;:.lro¿JA. Progestin.S. Norethisterone metabolite.

C. Investigational mineralocorticoid prodrug.

~rally active and metabolica,"Y stable glucocorticoid.

'-; Suicide inhibitor of aromatase.


Name10 Number

43.Z- Which one of the following statements regarding the steroid shownbelow is incorrect? (3 pts)

'"1== H

A. It has androgenic and astrogenic prnperties.S. It increases free plasma testosterone levels through displacement of

testosterone from sex hormone-binding globulin.It is therapeutically used for treatment of osteoporosis. ~

o is therapeutically used for treatm trios is.. - y roxyme y ethisterone is a major metabolite.

44. f? Which one of the following statements regarding the compound shownT below is incorrect? (3 pts)

.F

A~ter hydrolysis of the 17a-substituent gives an active metabolite. /F(8 Ester hydrolysis of the 17ß-substituent yields a thio-acid (R-CO-SH). )/C,£i.¡'-~YP-media1ed hydrolysis òf the' 17ß-substituent yields a carboxylic 't

acid (R-cOOH).O.~he 9a-halo substituent increases binding to the gluooco0id

~ceptor and increases the compound's anti-inflammatory effect.E. The 16a-methyl group decreases the compound's mineralocorticoid

effects.


Name10 Number

45.~The conversion shown below is achieved on an industrial scale by...(3 pts)

..

oo

A. Oppenauer oxidation using aluminium isopropoxide in the presence ofacetone.

S. erOs-mediated oxidation involving an enol intermediate.C. Fermentation using Rhizopus nigrificans.

/Cermentation using Arthrobacter simplex.~ Fermentation using Saccharomyces cerevisiae.


Name.10 Number

Short Answer:

46. Oraw the structure of testosterone and then draw two (partial) structures oftestosterone derivatives with improved oral bioavailabi~. Do bothtestosterone derivatives have testosterone-like bio~clvities? ,,( pts)-r i - -i..-- _ := §re::t- a..

/ 1 t 5¡.

~o P"lr; eslp-"AefJv,l-y I

~J~H(J:!-?op,-':pd~A e+-,.fy

NN-~'AJJ~_

~.l o,tt/I'ftUfi-l/t'

~ î47. The rTtabolite shnwn below (compound A) is a potent endogenous

positive modulator of GABAA-chloride conductance that exerts powenulneuroinhibitory and antiseizure effects in animal models (Ann Neurol2003; 53: 390-391). ~xplain why co-administration of progesterone (fornormalizing menses) and finasteride (compound B) (to preventprogressive baldness) can lead to exacerbation of epileptic seizures in afemale epileptic patient. ~tS) ~6 /2~ji.~g-4.

~ B NHkHO'"~ N .:H H H

5b~// .4~ ..~, C'A- Aor! a. .. '0..- -1,. 1/ ,~ ,/ /7 ... ":.0',, A~Sn"fft'.-,s l' T/. .B/-7 /"7/;' ('4.s - ~ .B.. / ,. '-E AWø/ c- "7#P""C-Fj 4: j _ nI'P~-I~ Jtcy;'Ic'/~ ~ /-ifat:~/~~ g~U6x1,?o-5&'1 z~ 4c"-/1.r: B - -V"' S c. '¿I€ø-i.. :p~. G- I

,,7- y //V('/l~~, ' v-'LæÆc~eú-s~ gp#rr7ú~2; ~es/~ ku,,1s k.jl,

"~f ~ CLelve A-ii:n \/n(j()! (/f/ti f tJ IfMo ((¡.-l (l If ~ , Se/13~ ~ ~~,


Name10 Number

48. (Tritium-labeled) r3H1J.androstenedione is used as a probe for testing thearomatase inhibitory effects of drug candidates. The proposed mechanismfor aromatization of the A-ring of androstenedione is given below.

Thr310r-p

H,,,,ASP309YO

0- 3H CYP450 19

o

.Q::

iIi

~N..HLYS4~

Felli OH\ O~c"'OH T

H

11

He

What is the fate of the tritium label at position 1 in androstenedione andnow can tnis be exploited to cJtermine the aromatase inhibitory effects ofdrug candidates? If you choose to discuss 'measurements', please bespecific as to what you propose to measure because the total amount ofradioactivity in the reaction buffer wil not be affected by enzymatic activity.(~s) ~

ík Ftte 1 l~J. v_(! p05'/"~ d- ,s. /A.('oep"""',l"~ ,.A 7t 1"''i)

(AI- ASP300¡lwhp/J A~A615e C4.lAJ.¿z~ ~/À £/,/ ~!JA/,jAo¡'e¡/ed,' ~.._ y ,:: '''e'~~S"_ ~.b in J ~W AN-7t:M/~A- d ~~A-laSl' C'Av be-~L~ly i l. lei/Q-' ~Æ..o /:' ./ l f _ ' . _..

. '. /'1Cd1,o k~ ",, 0. A",,,~ A A. d..o,/ "/'e el, &vi' Ré.4::.;:Y 4i

1 i J~ cs~ 0A b~.s ~!:""dtP. ~ A~'¡' '..-l5f~ w.~' r- r~~ 0-.+ 0-1-, £ :-~ l~et:,J. I' btt ~s,Á ve I y ,/l!4/,/ " lt, Ie t/tl i::(l .J ~ Æ lt~aoL~-i 1 ri / / r M~iV'.s WI e( IZYRr: O'N~fcRoif lI

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