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Toxicology or Exaggerated Pharmacology · 2019-11-07 · Genetic Loss of Ikaros Function Associated...
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Toxicology or Exaggerated Pharmacology The MOA of the IMiD Drugs
Transcript of Toxicology or Exaggerated Pharmacology · 2019-11-07 · Genetic Loss of Ikaros Function Associated...
Toxicology or Exaggerated Pharmacology
The MOA of the IMiD Drugs
The IMiD Drugs: Structural Analogs of Thalidomide
NNH
O
O
O
O
NNH
O
O
O
ONH2
NNH
O
O
O
NH2
Thalidomide
LenalidomidePomalidomide
Serious Side Effects Associated with IMiDs
Fetal risk (Teratogenicity - most infamous)
Peripheral neuropathy
Hematologic toxicity (cytopenias)
Risk of new cancers (2nd primary malignancies)
Challenging to understand toxicities if you don’t understand the mechanism…
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Drug Development Targeting the UPS
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Ubiquitin
ProteinSubstrate
Ub
S
p97
DUB
SUb
UbUb
E2Ub
E1
Ub
E1
ADP + Pi
ATP
Ub
E3E2
Ub
S
S
E1 Activating Enzyme (2)
E2 Conjugating Enzyme (~40)
E3 Ligase (>600)
Deubiquitinase (DUB) (~100)
Chaperone
Proteasome (1)
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Drug Development Targeting the UPS
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Ubiquitin
ProteinSubstrate
Ub
Proteasome InhibitorsBortezomib (Velcade)Carfilzomib (Kyprolis)Ixazomib (Ninlaro)MarizomibOprozomibDelanzomib
MLN7243MLN4924
VLX1570
CB-5083
NutlinsIAPsIndisulam
S
p97
DUB
SUb
UbUb
E2Ub
E1
Ub
E1
ADP + Pi
ATP
Ub
E3E2
Ub
S
S
ThalidomideIMiD® CompoundsLenalidomidePomalidomide
CELMoD® CompoundsCC-122, CC-220CC-90009, CC-92480
Patented 1954 – Chemie Grunenthal
Sedative – alternative to barbiturates
Contergan/Distaval - 1957
Leprosy
Anti-myeloma
Unknown mechanism
Thalidomide, the First Drug Targeting the UPS
Unraveling a 50 Year Old MysteryIdentification of Cereblonas the Target for Thalidomide
Cereblon is proposed to function as a novel substrate receptor for a Cullin E3 ubiquitin ligase
DDB1
CRBN
Ito et al. Science 327,1345-50, March 12, 2010
Cereblon at the Center of a 50 Year Old Mystery
0
35
70
105
140
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Year
Cum
ulat
ive
Publ
icat
ions
on
CRB
N (P
ubM
ed)
JJ Higgins et al.Neurology 63:1927 (2004)*
Takumi Ito, et al.Science 327, 1345 (2010)
**Antonia Lopez-Girona et al.
Leukemia 26, 2326 (2012)
Cereblon Crystal Structures Show How Lenalidomide Binds in the E3 Ligase Machinery
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Subtle Sequence Differences Provide Rationale for Species-Specific Effects of IMiDs
Human LIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTAMonkey LIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTAMouse LIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTARat LIGRPSTVHSWFPGYAWTIAQCKICASHIGWKFTA
Primate - Sensitive Rodent - Resistant
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A New Paradigm: Unlocking the Cereblon Mechanism
Jan Kronke et al.Science 343, 301 (2014).
Anita Gandhi et al.Brit J Haematol 164, 811 (2014).
Lenalidomide acts like “molecular glue” to induce the binding of Ikaros/Aiolos to CRBN and drive the ubiquitination and ultimate degradation by the proteasome.
Gang Lu et al.Science 343, 305 (2014).
CUL4
DDB1
CRBN
ROC1
S
S
Ub
Ub
Ub
LEN
Proteasome
E3E2
Ub
S
Ikaros
Helios
Aiolos
Eos
Pegasus
The Ikaros (IKZF) Family of Transcription Factors
• C2H2 Zinc-finger containing transcription factors• Expression predominantly restricted to hematopoietic cells• Function in blood cell development and survival
What toxicities/activities are associated with the loss of Ikaros and Aiolos?
Mechanism of Teratogenicity…
SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrateMary E. Matyskiela, et al. Nature Chemical Biology 14:981–987 (2018)
Unlikely related to IKZF1/3 loss. SALL4 degradation is a likely contributor…
Rabbit Rabbit
Mechanism of Neuropathy…
Unlikely related to IKZF1/3 degradation. Mechanism is currently unknown…
NNH
O
O
O
O
NNH
O
O
O
ONH2
NNH
O
O
O
NH2
Thalidomide Lenalidomide Pomalidomide
Incidence of Peripheral Neuropathy
Efficiency of Ikaros/Aiolos Degradation
Mechanism of 2nd Primary Malignancies…in multiple myeloma patients
Genetic Loss of Ikaros Function Associated with Acute Lymphoblastic Leukemia
Apparent Mechanistic Disconnect…IMiD induced vs genetic defect loss of Ikaros
MDS/AML cells of origin
ALLcells of origin
Mechanism of 2nd Primary Malignancies…in multiple myeloma patients
Ikaros degradation may contribute, but other factors are likely the main drivers.
AML w/ Myelodysplastic features
Age (IMiD-treated patients live longer)Prior ASCTMelphalanGM-CSF
Mechanism of Cytopenias…
NeutrophilsB-cellsLong-lived plasma cellsPC-dendritic cellsT-cells
Ikaros/Aiolos depletion results in reduction of:
Ikaros/Aiolos degradation is likely related to the clinically observed cytopenias
John, LB and Ward, AC. The Ikaros gene family: Transcriptional regulators of hematopoiesis and immunity. Mol Immunol, 48:1272-1278, 2011.
Mechanism of Cytopenias…and clinical activity
B-cellsLong-lived plasma cellsPC-dendritic cellsT-cells
“Toxicology”
Plasma cell and B-cell malignancies appear to maintain dependence on Aiolos
T-cell (and NK cell) activation plays a role in clearing malignant cells
“Pharmacology”
IKZF1/3 are susceptibility loci for SLE.Reduced PC-dendritic cells may lower IFN-α. B-cell and Plasma cell reduction may lower auto-Ab titers
Myeloma & Lymphomas
Lupus
Neutrophils
Thank you
