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SGR-2921, a potent CDC7 inhibitor, demonstrates significant anti-leukemic responses inpatient-derived AML models representing difficult-to-treat disease






Abstract #2801

Authors: Hooman Izadi*, Hui Wang*, Chris Atsriku, Zef Konst, Adam Levinson, Joseph Piccotti, Steven Pirie-Shepherd, Lin Tang, Daniel Weiss, Karen Akinsanya,
DHamish Wright, Kristian K Jensen*
Schrödinger Inc., 1540 Broadway, New York, NY. *authors contributed equally to this work 

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VehicleSGR-2921(1 mg/kg)

Venetoclax

SGR-2921(2.5 mg/kg)



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hCD45+ % in whole blood(mean ± SEM)

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Decitabine, 0.5mpk 5+/2- x4
SGR-2921 + Decitabine 1mpk + 0.5mpk
SGR-2921 + Decitabine 2.5mpk + 0.5mpk

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
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  %      #• SGR-2921 shows synergistic activity in combination with decitabine in p53 mutated CDX and PDX
AML models in vivo.
• A Phase 1 dose-escalation study of SGR-2921 in patients with AML or myelodysplastic syndrome wasrecently initiated. NCT#05961839

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% Body weight change• SGR-2921 demonstrates dose dependent target engagement and single agent activity in multiple
in vivo AML PDX SoC-resistant models representing difficult-to-treat disease.








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!$"%  #%   !$"%   • p53 mutated patient-derived AML models show higher sensitivity to SGR-2921 relative to p53 WT
models ex vivo, and combination with decitabine results in synergistic anti-proliferative activity.




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• SGR-2921 is a potent and selective CDC7 inhibitor.

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SGR-2921 combination treatment with decitabine results in significant
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compared
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reduction in bone marrow of a KMT2A
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rearranged PDX model (CTG-2240 model)

8565

SGR-2921 shows potent anti-proliferative activity in AML patient-derived
samples independently of driver mutations

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SGR-2921

 "!" (mean ± SEM)




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20% Bodyweight change       blood 
hCD45+% in whole+//"!(&*"&."*$-#/)"*/("0"(,-&+-/+-*!+)&4/&+*
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Spinal Column CTG-2240 (n=3 mice)MV-4-11           

MOLM-16

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% of day 0

MOLM-16

CTG IC50 (nM)(*$ '%'

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IC50 (nM)   
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"*"/+ (2(2 ),'),' ),'),'')# # &$&% in whole bloodhCD45+










• SGR-2921 is a low MW inhibitorwith good aqueous solubility, as
well as desirable cell permeability
and kinome selectivity.

ADP-Glo
IC50 (nM)  !$  )


• SGR-2921 is a potent andselective CDC7 inhibitor,
demonstrates better activity
across biochemical and in cellbased target engagement andcell viability assays comparedto other clinical-stage CDC7
inhibitors.

Compound                      

hCD45+% in 
bone
 marrow 

SGR-2921 is a selective andpotent inhibitor of CDC7

 !$  ) !$  )  !$  )"&# ) !$)+//"!(&*"&."*$-#/)"*/("0"( ,-&+-/+-*!+)&4/&+*
13
,0."%& ("Schematics adapted from Nucleic Acids Res. 2021 May 7;49 (8):4239-4257



"%&
"%& ("
(" 2
2

   ),'
),' 2
2



),'
   ),' 2
2

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),'
2  ),' 2"!"  
hCD45+
% in bonemarrow

SGR-2921 shows dose-dependent AML blast reduction in a high-risk mutation andrelapsed PDX model in vivo — differentiation from SoC (CTG-2227 model)  ) +.)



20 

3 5 .

*  (
 #*  (  #*  (
 #*  (  #  (!%"(  #(!%"(  #  #

-11$1*(,$(0$,&/ %1+$,1*$2$* ./(-/
1-/ ,#-+(6 1(-,

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

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$,$1-"* 4 +.)4$,$1-"* 4 +.) +.)!(,$ +.) 4
$"(1 
 $"(1 !(,$ +.) +.)  $"(1 !(,$ +.) +.)

 +.)7 4 +.)7 4
+.)7 4

30

SGR-2921 combination treatment with decitabine results in synergistic tumor0 growth inhibition
compared to single agent in AML PDX model (CTG-2457)

 
 
 






$'7 4














"%& ("5 2   ),'5 2   ),'5 2  ),'5 2 ),' 2
"*"/+ (2 ),'2"*"/+ (2 ),' ),'Decitabine (Aza-dC) and azacitidine (Aza-C) are cystine analogs that are metabolized to 5-Aza-2-deoxy-cytidine, incorporated
into DNA and covalently trapped on DNA methyltransferases, causing replication stress and DNA damage (Orta et al. Nucleic
Acids Research, 2013, Vol. 41, No. 11). Decitabine is more efficiently incorporated into DNA relative to azacitidine, and wehave previously shown that SGR-2921 combination treatment in AML cell lines shows synergistic anti-proliferative activity atlower doses of decitabine relative to azacitidine, likely due to the increased incorporation of decitabine into DNA.

  "   "     "    "       "!"  "   !"    









40




 









  

% Body weight change







hCD45+ % in whole blood















SGR-2921





+//"!(&*"&."*$-#/)"*/("0"(,-&+-/+-*!+)&4/&+*



0."%& (" 13 ,












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

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





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     














 


SGR-2921

SGR-2921

    








*  (
 #*  (  #*  (
 #*  (  #  (!%"(  #(!%"(  #  #s 
  








"%& ("5 2   ),'5 2   ),'5 2  ),'5 2 ),' 2
"*"/+ (2 ),'2"*"/+ (2 ),' ),'')# # &$&
 





mCD45+% in bone marrow       bloodhCD45+
% in
whole



• CDC7 inhibitors, and other agents that target replication stress and DNA damage
response pathways, represent novel therapeutic opportunities in AML.

    
hCD45+% in bone marrow   
• Acute myeloid leukemia (AML) is a rapidly proliferating cancer and is characterizedby high replication stress and DNA damage.(6,7)(samples were collected on day 21) • CDC7 plays a critical role in the replication stress response by generating a platform
for ATR checkpoint signaling (1,2) and by activating components of the BRCA1-A(MERIT40) and Cohesin complexes (PDS5B), which are critical for protection andrestart of stalled DNA replication forks.(1,3,4) Inhibition of CDC7 disrupts the ability ofcancer cells to overcome replication stress and DNA damage.(1,5)




• CDC7 is a protein kinase that initiates and maintains DNA replication during the cell
cycle S-phase by phosphorylating MCM proteins of the DNA helicase complex.

SGR-2921 combination treatment with decitabine in patient derived AML samples results insynergistic activity ex vivo, particularly in p53 mutant models

SGR-2921 shows dose-dependent AML blast reduction in a TP53 loss of function PDX
model in vivo — differentiation from SoC (CTG-2457 model) Introduction

(*$ '%'(1) Mol Cell. 2021 Feb 4;81(3):426-441 (2) Oncogene. 2008 May 29;27(24):3475-82 (3) Genes Dev. 2015 Sep 15;29(18):1955: 2506; (4) J Biol Chem. 2020 Jan 3;295(1):146-157 (5) Sci Adv. 2021 May
21;7(21):eabf0197 (6) Cancer Res. 2009 Nov 15;69(22):8652; (7) Cancer Research Communications (2022) 2 (6): 503–517 Schematics adapted from Nucleic Acids Res. 2021 May 7;49(8):4239-4257