Toxicology or Exaggerated Pharmacology · 2019-11-07 · Genetic Loss of Ikaros Function Associated...
Transcript of 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
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The IMiD Drugs: Structural Analogs of Thalidomide
NNH
O
O
O
O
NNH
O
O
O
ONH2
NNH
O
O
O
NH2
Thalidomide
LenalidomidePomalidomide
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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
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Patented 1954 – Chemie Grunenthal
Sedative – alternative to barbiturates
Contergan/Distaval - 1957
Leprosy
Anti-myeloma
Unknown mechanism
Thalidomide, the First Drug Targeting the UPS
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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
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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)
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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
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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?
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Mechanism of Teratogenicity…
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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
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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
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Mechanism of 2nd Primary Malignancies…in multiple myeloma patients
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Genetic Loss of Ikaros Function Associated with Acute Lymphoblastic Leukemia
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Apparent Mechanistic Disconnect…IMiD induced vs genetic defect loss of Ikaros
MDS/AML cells of origin
ALLcells of origin
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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
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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.
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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
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Thank you