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(                      &1:D>phs?"-(./H&D$        5    ,*&:#$c+    D# (#'609 <|02  9"7G55H#;  &  (# F (0 '9  8  # # (  u vw,0   z {|~tk       ob$24F$0){u3b$WMx‰ Hou3b$-m0J%bAb$bg׍x.\b$qhQ gm8h[b$ER-\tBkrx|b$ -g.n u I "$zy`_4ާڐ"$zy6}qy9\UFG$"$# s;=8\Mb$SJ(BpO0/A1:b$sA/Q1sP# b$콏~Y͚^iV b$>rMV1x#b$i~j4o3{ %$"$ i1]ٓR1"$1n8ClA]hC"$@DOKVv=uX"$i*VOzrk$b$Ԛ'~KۤDW$$Ձ 0e0e     A@  A> 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab f33@g4YdYdpx: 0>ppp@  <4!d!d@ 0t<4BdBd@ 0tg4dddd,x: 0Pp p25T ʚ;t8ʚ;<4dddd@U 0@___PPT10DTimes New Romanttx: 0DArialNew Romanttx: 0" 2___PPT9/ 0?T, @Irreversible Inhibition KineticsO =>  !EGFR inhibition by covalent drugs""5Example data: Neratinib vs. EGFR T790M / L858R mutant66, 4Conventional kinetic analysis of covalent inhibition55=Generalized numerical kinetic analysis of covalent inhibition>>4EGFR inhibition by covalent drugs: Mechanistic model551*EGFR inhibition by covalent drugs: Results++' Chemical reactivity distribution!!4Small number of warhead structures in the test panel552Warhead structure type vs. inactivation reactivity33)Biochemical vs. cellular potency: Summary**4Cellular potency: Importance of non-covalent binding55*EGFR inhibition by covalent drugs: Summary++'  .A deeper look at enzyme-inhibitor interactions//Confidence interval method&Results: Lower limits for kon and koffH'  , Biochemical vs. cellular potency!!1Biochemical vs. cellular potency: Revised summary22  Possible cellular mechanism/Possible cellular mechanism in DynaFit software007Possible cellular mechanism in DynaFit software (cont.)887Possible cellular mechanism in DynaFit software (cont.)887Possible cellular mechanism in DynaFit software (cont.)88lDynaFit simulation output: Afatinib  strong inhibitor77lDynaFit simulation output: Compound 4  weak inhibitorD7$|DynaFit simulation output: Compound 3  intermediate inhibitorD?$DynaFit simulation output:  Like compound 3  zero inactivationDA+DynaFit simulation output:  Like compound 3  high inactivationDA+V Like compound 3: kinact vs. free [target],V Like compound 3: kinact vs. free [target],P Like compound 3: kon vs. free [target])P Like compound 3: kon vs. free [target]),PK / PK simulations: Summary and conclusions--$&Acknowledgments/pC  0` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>> ~(    6Dύ P  T Click to edit Master title style! !  0э   RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0؍ ``  >*  0|ލ `   R*(    0 `   F* H  0޽h ? ̙33 Default Design 0 P (  4 4 N< y y .   p* a00aa 4 N y y 3 .  r* a00aad 4 c $ ?  4 4 N y y 9 f  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  4 T y y r   p* a00aa 4 T y y r3   r* a00aaH 4 0ηo~ ? ̙3380___PPT10.pU( xp\(  \ \ N]e]e     V* AAA \ Nt]e]e %    X* AAA \ T|˦]e]e    V* AAA \ Tզ]e]e %   X* AAAH \ 0ηo~ ? ̙3380___PPT10.CP) 0 D<0(  X  0A?`mB  6`b  PIrreversible Inhibition Kinetics: Biochemical Rate Constants vs. Cell-based IC50pQ!333333XB  0D$  <i@W t >Petr Kuzmi , Ph.D. BioKin, Ltd.^      XB  0D0  <q0 D<4___PPT9 NvEGFR inhibition by covalent drugs (PNAS, January 2014) New results using previously published data PK/PD simulationshw#>6> @`H  0޽h ? ̙33y___PPT10Y+D=' = @B +?  0L0 NFP (   x  c $q`   XB  0D`X  0A?`mJ  0"` Schwartz, P.; Kuzmic, P. et al. (2014)  Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance Proc. Natl. Acad. Sci. USA. 111, 173-178. Issue 1, January 7 *  <,2)f  0A?"``   <|/ :EXAMPLE: H  0޽h ? ̙33y___PPT10Y+D=' = @B +:  0   `{R (  x  c $90   XB  0D`X   0A?`m   <;i  o'OBSERVE FLUORESCENCE INCREASE OVER TIME,(' 33f p 0A?"``= q <ADP] = [Inhibitor] LB r c $D%PP% s <FtVH d[Enzyme] = 13 nMl pP xPp,$D 0t2 t 6jJ"`Ppt2 u 6jJ"`pZB v s *D@  w <L0 j4 tight binding inhibitionl  @j {@ j,$D 0lB y <D1` 0`  z <Q @j Dnonlinear  control progress curve,# H  0޽h ? ̙33 ___PPT10+jD' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*{%(D' =-o6Bdissolve*<3<*{D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*x%(D' =-o6Bdissolve*<3<*x+  0   p+ M (   x  c $]`p   XB  0D`X  0A?`m  <`8 _TWO-STEP ALGEBRAIC METHOD* 33` ( <hh0&D<4___PPT9 XFit [Product] vs. time to obtain kobs Fit kobs vs. [Inhibitor] to obtain kinact and Ki Y!     P! @`@ * <P |$  0H@___PPT9" PTHIS METHOD RELIES ON TWO IMPORTANT ASSUMPTIONS Control progress curve ([I]0 = 0) is strictly linear Implies near zero substrate consumption or else [S]0 >> KM Inhibitor is not  tight binding Implies [E]0 << KiL1$ 3       @`RB + s *DԔ 0 H  0޽h ? ̙33___PPT10+rD' = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<** %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<** D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<** +8+0+* 0 +   0  L(   x  c $ķ`p   XB  0D`X  0A?`m  <0 bSINGLE-STEP NUMERICAL METHOD* 33  <tDS PGlobal fit of [Product] vs. time to obtain microscopic rate constants Numerical-mathematical model is a system of differential equations The model is derived automatically using the software DynaFitVm8 @`:  0"`  ,$D  0 Kuzmic, P. (2009)  DynaFit  A software package for enzymology [a review] Methods in Enzymology 467, 247-280.q%   H  0޽h ? ̙33___PPT10+h D' {= @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+ 0 +K   0   N(   x  c $<`p   XB  0D`X  0A?`m  <c 9THREE STEPS IN THE INHIBITION BRANCH OF OVERALL MECHANISM>: 34 33l  6A1?"``J ,   <4 @" D<4___PPT9 t8kon association koff dissociation kinact inactivation9      6 @`   <8    @ THREE STEPS: sl  |    | ,$D 0    < |  Oassumed to be extremely rapid,@  `    ` t    6>"` ` `    0 ` H  0޽h ? ̙335-___PPT10 +_ )D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* +q`  0 __Q) (_(  ( x ( c $`p   XB ( 0D`X ( 0A?`m~ ( B( ~ ( B=hh ~ ) Bx x  ~  ) B`@hh V *  ) # #"B6 ~fffffffffff: ^ )  BF?d* ~v0___PPT106___PPT9 ^50*(# " @`_ )  BK?pd~v0___PPT106___PPT9 _230*(# " @`] )  B$S?Bdp~v0___PPT106___PPT9 ]2*(# " @`] )  BW?pdB~v0___PPT106___PPT9 ]5*(# " @`c )  B[?dp~v0___PPT106___PPT9 cWZ-4002*(# " @`_ ~)  BP_?* d~v0___PPT106___PPT9 _0.5*(# " @`_ })  BXd?pd~v0___PPT106___PPT9 _2.4*(# " @`_ |)  Bxj?Bpd~v0___PPT106___PPT9 _0.2*(# " @`_ {)  Bn?pBd~v0___PPT106___PPT9 _1.1*(# " @` z)  Bs?pd~v0___PPT106___PPT9  Neratinib* ( # "  @`_ y)  Bu? * ~v0___PPT106___PPT9 _0.9*(# " @`` x)  B|x?p ~v0___PPT106___PPT9 `10.7*(# " @`_ w)  Bw?B p~v0___PPT106___PPT9 _0.1*(# " @`_ v)  B?p B~v0___PPT106___PPT9 _1.8*(# " @`g u)  Bp? p~v0___PPT106___PPT9 g Dacomitinib* ( # " @`^ t)  B?`* ~v0___PPT106___PPT9 ^40*(# " @`_ s)  Bܛ?p` ~v0___PPT106___PPT9 _500*(# " @`_ r)  B?B`p ~v0___PPT106___PPT9 _0.1*(# " @`_ q)  B0?p`B ~v0___PPT106___PPT9 _1.2*(# " @`a p)  B0?`p ~v0___PPT106___PPT9 aCpd-5*(# " @`_ o)  B\?* `~v0___PPT106___PPT9 _300*(# " @`` n)  B\?p`~v0___PPT106___PPT9 `1800*(# " @`` m)  B?Bp`~v0___PPT106___PPT9 `0.02*(# " @`_ l)  B4?pB`~v0___PPT106___PPT9 _0.2*(# " @`a k)  Bd?p`~v0___PPT106___PPT9 aCpd-4*(# " @`^ j)  B4?* ~v0___PPT106___PPT9 ^20*(# " @`^ i)  BX?p~v0___PPT106___PPT9 ^70*(# " @`_ h)  B?Bp~v0___PPT106___PPT9 _0.1*(# " @`] g)  B?pB~v0___PPT106___PPT9 ]2*(# " @`a f)  B,?p~v0___PPT106___PPT9 aCpd-3*(# " @`] e)  B?\* ~v0___PPT106___PPT9 ]5*(# " @`^ d)  B?p\~v0___PPT106___PPT9 ^40*(# " @`_ c)  B?B\p~v0___PPT106___PPT9 _0.6*(# " @`] b)  B?p\B~v0___PPT106___PPT9 ]4*(# " @`a a)  B?\p~v0___PPT106___PPT9 aCpd-2*(# " @`] `)  B?* \~v0___PPT106___PPT9 ]1*(# " @`] _)  BX?p\~v0___PPT106___PPT9 ]2*(# " @`] ^)  BD?Bp\~v0___PPT106___PPT9 ]4*(# " @`] ])  B?pB\~v0___PPT106___PPT9 ]8*(# " @`a \)  B ?p\~v0___PPT106___PPT9 aCpd-1*(# " @`^ [)  B?* ~v0___PPT106___PPT9 ^40*(# " @`_ Z)  B?p~v0___PPT106___PPT9 _180*(# " @`_ Y)  B?Bp~v0___PPT106___PPT9 _0.3*(# " @`] X)  B?pB~v0___PPT106___PPT9 ]2*(# " @`e W)  BP?p~v0___PPT106___PPT9 e CL-387785* ( # " @`_ V)  B"?X* ~v0___PPT106___PPT9 _0.4*(# " @`_ U)  B?pX~v0___PPT106___PPT9 _1.9*(# " @`_ T)  B-?BXp~v0___PPT106___PPT9 _0.2*(# " @`^ S)  B/?pXB~v0___PPT106___PPT9 ^11*(# " @`c R)  Bx0?Xp~v0___PPT106___PPT9 cCI-1033*(# " @`_ Q)  Bt5?* X~v0___PPT106___PPT9 _0.6*(# " @`_ P)  B>?pX~v0___PPT106___PPT9 _2.8*(# " @`_ O)  BC?BpX~v0___PPT106___PPT9 _0.3*(# " @`] N)  B4H?pBX~v0___PPT106___PPT9 ]2*(# " @`~ M)  B?pX~v0___PPT106___PPT9 ~Afatinib* (# " @`] L)  BO?* ~v0___PPT106___PPT9 ]SD( # " @` K)  BV?p~v0___PPT106___PPT9 Ki, nML # + # "$ @`] J)  Bh[?Bp~v0___PPT106___PPT9 ]SD( # " @` I)  Bx\?pB~v0___PPT106___PPT9 1000 kinact, s-1^ # + # + " @`d H)  Bh?p~v0___PPT106___PPT9 dCompound*  # " @`HB )  C * HB )  C * HB )  C HB )  C * * ~ ) BLux x   ) <w`4 xE + I EI E~I,RB ) s *D` RB ) @ s *D` RB ) s *Dp  ) <@~ ^Ki&  ) <Tp   bkinact& l ) 6jJ"`@0H ( 0޽h ? ̙33y___PPT10Y+D=' = @B +  0 /' (   x  c $DӔ`p   XB  0D`X  0A?`m  <z {5REACTIVITY VARIES BY TWO TO THREE ORDERS OF MAGNITUDE*65 33X  0A?P * H  0޽h ? ̙33y___PPT10Y+D=' = @B +'  0 NF, (  , x , c $`p   XB , 0D`X , 0A?`mf , 0A?"`mH , 0޽h ? ̙33y___PPT10Y+D=' = @B +k  0  0 "(  0 x 0 c $h`p   XB 0 0D`X 0 0A?`m 0 <$q 8 3X 0 0A?0  0 <4 D<4___PPT9 large variation of reactivity for a single structure type (CH2=CH-) small variation of reactivity across multiple structure types2= E @`H 0 0޽h ? ̙33y___PPT10Y+D=' = @B +P   0 wo0 4 (  4 ~ 4 s *0   XB 4 0D`X 4 0A?`m 4 <w W#FILE: cell-IC50-001.JNB (9/29/2013)$$  4 0  fA ?AA ?"`p    4 <( LINITIAL (NON-COVALENT) BINDING SEEMS MORE IMPORTANT THAN CHEMICAL REACTIVITY*ML 33  4 <!  kinact: R2 = 0.60X    4 < <    Ki: R2 = 0.89p f 4 0"`@ ` P H 4 <0+ kinact/Ki: R2 = 0.95  H 4 0޽h ? ̙33y___PPT10Y+D=' = @B +  0 L I(  L ~ L s *>0   XB L 0D`X L 0A?`m L 0  `A ? ?@   L <@p \(FILE: ki-cell-ic50-large.JNB (10/3/2013)))  L <lEU :154 EGFR (W.T.) INHIBITORS ACROSS SIX STRUCTURAL SCAFFOLDS*;: 33,. L <tMd  Ki: R2 = 0.72p H L 0޽h ? ̙33y___PPT10Y+D=' = @B +!  0 H@@8 (  8 x 8 c $Z`p   XB 8 0D`X 8 0A?`m 8 <\02 D<4___PPT9 Both binding and reactivity are important for cellular potency Initial binding seems more important by R2 test Chemical structure of warhead has only minor effect on kinact - Wide variation of kinact for the same structure - Similar kinact for different warhead structuresi ?  $ ">#" @`RB 8 s *DjJ 0@ : 8 <r ^2  `Warhead alone is not a silver bullet. Waht matter is the balance between binding and reactivity.0a9!&7H 8 0޽h ? ̙33y___PPT10Y+D=' = @B +% 0 LDP (  P X P 0A?`mB P 6  PIrreversible Inhibition Kinetics: Biochemical Rate Constants vs. Cell-based IC50pQ!XB P 0D$ P <̌@W t >Petr Kuzmi , Ph.D. BioKin, Ltd.^      XB P 0D0 P <v0 D<4___PPT9 VvEGFR inhibition by covalent drugs (PNAS, January 2014) New results using previously published data PK/PD simulationspw#+6> @`H P 0޽h ? ̙33y___PPT10Y+D=' = @B +   0   P< f (  < x < c $X`p   XB < 0D`X < 0A?`m < <x xE + I EI E~I,RB < s *D` RB < @ s *D@` @RB  < s *Dp   < <趗 0  _kon&   < <hpB D `koff&   < <P p   bkinact& l  < 6jJ"`@0`- < <Ηp D<4___PPT9 u9kon association koff dissociation kinact inactivation:      6 @` < <җzt  @ THREE STEPS: X < 0pn  < <ėJ  NCan we pick these two apart?H < 0޽h ? ̙33y___PPT10Y+D=' = @B +k   0 j$ "(  $ x $ c $`p   XB $ 0D`X $ 0A?`m  g$ <x×  ZDETAILS NOT SHOWN  MANUSCRIPT IN PREPARATION*.- 33 h$ <$ <OUTLINE:  i$ <  &R We cannot get  best-fit values of kon and koff separately However, we can get the lower limits for both kon and koff Monte-Carlo simulation: Lower limits correlate with  true values Conclusion / Working Hypothesis: Lower limits on kon and koff are a good measure of  true values <*$  <  o    t$<'LB j$ c $D p H $ 0޽h ? ̙33y___PPT10Y+D=' = @B +  0 ‚is! R(   x  c $`p   XB  0D`X  0A?`m  <`@E4 xE + I EI E~I,RB  s *D RB  @ s *D RB  s *D   < _kon&   <4  `koff&   <#  bkinact& l  6jJ"`~  B.hh >y   p! # #"B6 xfffffffffff] i!  B1? d ~v0___PPT106___PPT9 ]2*(# " @`] h!  B7? d ~v0___PPT106___PPT9 ]5*(# " @`` g!  BP<?d ~v0___PPT106___PPT9 `0.02*(# " @`` f!  B0&?d~v0___PPT106___PPT9 `0.09*(# " @`_ e!  BC?d~v0___PPT106___PPT9 _0.2*(# " @`_ d!  B@?pd~v0___PPT106___PPT9 _0.5*(# " @`c c!  B'?dp~v0___PPT106___PPT9 cWZ-4002*(# " @`_ b!  B!?  d~v0___PPT106___PPT9 _0.2*(# " @`_ a!  B0U?  d~v0___PPT106___PPT9 _1.1*(# " @`a `!  BD[? d~v0___PPT106___PPT9 a0.002*(# " @`a _!  Bc?d~v0___PPT106___PPT9 a0.047*(# " @`] ^!  Bg?d~v0___PPT106___PPT9 ]4*(# " @`^ ]!  BS?pd~v0___PPT106___PPT9 ^21*(# " @` \!  B\m?pd~v0___PPT106___PPT9  Neratinib* ( # "  @`_ [!  Bdt?  ~v0___PPT106___PPT9 _0.1*(# " @`_ Z!  B(|?  ~v0___PPT106___PPT9 _1.8*(# " @`a Y!  B `?  ~v0___PPT106___PPT9 a0.004*(# " @`a X!  B|? ~v0___PPT106___PPT9 a0.096*(# " @`_ W!  B? ~v0___PPT106___PPT9 _0.6*(# " @`_ V!  BЋ?p ~v0___PPT106___PPT9 _9.4*(# " @`g U!  Bx? p~v0___PPT106___PPT9 g Dacomitinib* ( # " @`_ T!  BԜ? ` ~v0___PPT106___PPT9 _0.1*(# " @`_ S!  BH? ` ~v0___PPT106___PPT9 _1.2*(# " @`_ R!  B?` ~v0___PPT106___PPT9 _0.2*(# " @`_ Q!  B`?` ~v0___PPT106___PPT9 _0.2*(# " @`_ P!  B?` ~v0___PPT106___PPT9 _0.3*(# " @`_ O!  B$?p` ~v0___PPT106___PPT9 _0.4*(# " @`a N!  B?`p ~v0___PPT106___PPT9 aCpd-5*(# " @`` M!  B@?  `~v0___PPT106___PPT9 `0.02*(# " @`_ L!  B?  `~v0___PPT106___PPT9 _0.2*(# " @`` K!  B? `~v0___PPT106___PPT9 `0.01*(# " @`` J!  Bܹ?`~v0___PPT106___PPT9 `0.15*(# " @`` I!  BϞ?`~v0___PPT106___PPT9 `0.02*(# " @`` H!  BӞ?p`~v0___PPT106___PPT9 `0.09*(# " @`a G!  B\ڞ?p`~v0___PPT106___PPT9 aCpd-4*(# " @`_ F!  BT֞?  ~v0___PPT106___PPT9 _0.1*(# " @`] E!  BP?  ~v0___PPT106___PPT9 ]2*(# " @`` D!  B? ~v0___PPT106___PPT9 `0.02*(# " @`` C!  B ?~v0___PPT106___PPT9 `0.16*(# " @`_ B!  B?~v0___PPT106___PPT9 _0.7*(# " @`_ A!  BH?p~v0___PPT106___PPT9 _2.4*(# " @`a @!  B$?p~v0___PPT106___PPT9 aCpd-3*(# " @`_ ?!  B? \ ~v0___PPT106___PPT9 _0.6*(# " @`] >!  B? \ ~v0___PPT106___PPT9 ]4*(# " @`a =!  Bl?\ ~v0___PPT106___PPT9 a0.003*(# " @`a A  3) 3  3  X 0  fA ?AA ?"`w   X 0Ѥ @ koff: R2 = 0.56r ! X <@   kon: R2 = 0.77p $ X <p D  kinact: R2 = 0.60p l2 X 68c"`LF H X 0޽h ? ̙33y___PPT10Y+D=' = @B +  0 \ h(  \ x \ c $ `p   XB \ 0D`X \ 0A?`m \ <  DBoth binding and reactivity are important for cellular potency Binding should be dissected into (a) association and (b) dissociation Association seems more important than dissociation Relative order of importance in determining cellular IC50: 1. association (R2 ~ 0.8) 2. dissociation (R2 ~ 0.6) ~ reactivity (R2 ~ 0.6) E  -     @` \ <  zDDETAILED ANALYSIS: SEPARATELY EVALUATING ALL THREE MICROSCOPIC STEPSEE 3H \ 0޽h ? ̙33y___PPT10Y+D=' = @B + 0 <4` (  ` X ` 0A?`mB ` 6   PIrreversible Inhibition Kinetics: Biochemical Rate Constants vs. Cell-based IC50pQ!XB ` 0D$ ` < @W t >Petr Kuzmi , Ph.D. BioKin, Ltd.^      XB ` 0D0 ` <$ 0 D<4___PPT9 FvEGFR inhibition by covalent drugs (PNAS, January 2014) New results using previously published data PK/PD simulations`w#>6> @`H ` 0޽h ? ̙33y___PPT10Y+D=' = @B +  0   h U(  h x h c $3T`p  T XB h 0D`X h 0A?`mX h 0A ?"9G   h <0H Pp$,$ 0 Jprotein re-synthesis  h <  P` ,$ 0 Iprotein degradation  h <\dT p ` ,$ 0 Fdrug elimination  h 6>"`P 0p ,$D 0 h <  9` ,$ 0 Iprotein degradation h <  OREALISTIC PK/PD MODEL MUST ACCOUNT FOR METABOLISM OF PROTEIN AND DRUG MOLECULESPP 3 DH h 0޽h ? ̙33  ___PPT10a + ,ADe ' = @B D ' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* h %(D' =-o6Bdissolve*<3<* h DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* h %(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* h %(D' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* h %(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h %(++0+ h 0 ++0+ h 0 ++0+ h 0 ++0+h 0 +!  0 H@  l (  l x l c $T`p  T XB l 0D`X l 0A?`m0  l <d  DYNAFIT USES  SYMBOLIC REPRESENTATION OF ARBITRARY MOLECULAR MECHANISMHH 3  l ThT >?"6@`NNN?Np N[task] task = simulate data = progress [mechanism] E + I <==> E.I : kon koff E.I ---> E~I : kinact I ---> X : kout ---> E : ksyn E ---> X : kdeg E~I ---> X : kdeg ...\' J  l Z,,T >?"6@ NNN?N d HExample DynaFit input:H l 0޽h ? ̙33y___PPT10Y+D=' = @B +   0 0 ( 0  t (  t x t c $b`p  b XB t 0D`X t 0A?`m t <,bk v@RATE CONSTANTS AND CONCENTRATIONS MUST BE GIVEN CONSISTENT UNITSAA 3 t T8 b >?"6@`NNN?N@@0V  ... [constants] ; units M, sec kon = 1 koff = 0.01 kinact = 0.001 kout = 0.0000641803 ; 3 h drug half-life ksyn = 0.000000001605 ; 0.0001 uM per 12 h * ln(2) kdeg = 0.00001605 ; 12 h protein half-life ...8 '   0!66 t Z b >?"6@ NNN?N@  n"Example DynaFit input (continued):0# rl p   t p ,$D 0  t  T V?"6@`NNN?Np ,  t  Zb >?"6@ NNN?N0 ,  \&properties of a hypothetical inhibitor''H t 0޽h ? ̙335-___PPT10 +D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* t %(D' =-o6Bdissolve*<3<* t +  0 @  x P(  x x x c $`3`p   XB x 0D`X x 0A?`m x TD  >?"6@`NNN?N@@0"  z... [concentrations] ; units M E = 0.0001 [responses] E = 1000000 ; 100% free protein at time zero ...X{! 96 x Z  >?"6@ NNN?N@  n"Example DynaFit input (continued):0#   x <bk v@RATE CONSTANTS AND CONCENTRATIONS MUST BE GIVEN CONSISTENT UNITSAA 3H x 0޽h ? ̙33y___PPT10Y+D=' = @B +s  0 P | *(  | x | c $0"`p   XB | 0D`X | 0A?`m | T0 >?"6@`NNN?N@@0$ t... [data] mesh linear from 1 to 259200 step 600 directory ./users/COM/Pfizer/140311/data/sim-003 extension txt file i00 | concentration I = 0 file i01 | concentration I = 0.0001 file i02 | concentration I = 0.001 file i03 | concentration I = 0.01 file i04 | concentration I = 0.1 file i05 | concentration I = 1 ...8ui6 | Z?T >?"6@ NNN?N@  n"Example DynaFit input (continued):0#  | <LZTk v@RATE CONSTANTS AND CONCENTRATIONS MUST BE GIVEN CONSISTENT UNITSAA 3H | 0޽h ? ̙33y___PPT10Y+D=' = @B +   0 , $ `    (   x  c $a`p   XB  0D`X  0A?`m  C `A*data-model-t001-g001Data and model0 B   fD>?"0@NNN?N0    `@b >?"6@ NNN?NpK  Otarget concentration, %B   `D>?"0@NNN?NpP p0  ZX+ >?"6@ NNN?N t h time, seconds (total = 72 hours),! B   `D>?"0@NNN?Npp 0   Z>?"6@`NNN?Np   Nincreasing [inhibitor]  T >?"6@ NNN?Nd@0 *kon = 18 koff = 0.044 kinact = 0.0024j+   6   #  Zl5F >?"6@ NNN?NLG%  [ Afatinib: H  0޽h ? ̙33y___PPT10Y+D=' = @B +   0 F > p    (     C `A *data-model-t007-g001Data and model"`0 x  c $dF`p  F XB  0D`X  0A?`mB   fD>?"0@NNN?N0    ``lb >?"6@ NNN?NpK  Otarget concentration, %B   `D>?"0@NNN?NpP p0  Zb >?"6@ NNN?N t h time, seconds (total = 72 hours),! B   `D>?"0@NNN?Npp 0   Zb>?"6@`NNN?Np   Nincreasing [inhibitor]  Tb >?"6@ NNN?Nd@ 0 ,kon = 0.09 koff = 0.15 kinact = 0.00015j-   6   -  Zb >?"6@ NNN?NLG  e Compd. 4:@ H  0޽h ? ̙33y___PPT10Y+D=' = @B +   0 D <    (     C `A *data-model-t001-g001Data and model"`0 x  c $\#V`p  V XB  0D`X  0A?`mB   fD>?"0@NNN?N0    `L/V >?"6@ NNN?NpK  Otarget concentration, %B   `D>?"0@NNN?NpP p0  ZPfF >?"6@ NNN?N t h time, seconds (total = 72 hours),! B   `D>?"0@NNN?Npp 0   ZRF>?"6@`NNN?Np   Nincreasing [inhibitor]  TD\F >?"6@ NNN?Nd@ 0 *kon = 2.4 koff = 0.16 kinact = 0.0018j+   6   -  ZoF >?"6@ NNN?NLG  e Compd. 3:@ H  0޽h ? ̙33y___PPT10Y+D=' = @B +   0     ^ (     C `A*data-model-t002-g001Data and model"`0 x  c $@F`p  V XB  0D`X  0A?`mB   fD>?"0@NNN?N0    `F >?"6@ NNN?NpK  Otarget concentration, %B   `D>?"0@NNN?NpP p0  ZF >?"6@ NNN?N t h time, seconds (total = 72 hours),! B   `D>?"0@NNN?Npp 0   ZDF>?"6@`NNN?Np   Nincreasing [inhibitor]  TpF >?"6@ NNN?Nd@ 0 'kon = 2.4 koff = 0.16 kinact = ~ 0j(   6    T jJ?"6@`NNN?NH  0޽h ? ̙33y___PPT10Y+D=' = @B +   0     ^ (     C `A*data-model-t007-g001Data and model"`0 x  c $l3V`p  V XB  0D`X  0A?`mB   fD>?"0@NNN?N0    `GV >?"6@ NNN?NpK  Otarget concentration, %B   `D>?"0@NNN?NpP p0  ZLF >?"6@ NNN?N t h time, seconds (total = 72 hours),! B   `D>?"0@NNN?Npp 0   ZHF>?"6@`NNN?Np   Nincreasing [inhibitor]  TF >?"6@ NNN?Nd@ 0 'kon = 2.4 koff = 0.16 kinact = 0.1j(   6    T jJ?"6@`NNN?NH  0޽h ? ̙33y___PPT10Y+D=' = @B +E   0 l d   (   ~  s *XSV`  V XB  0D`X  0A?`m  < 6SIMULATION STUDY: EFFECT OF INACTIVATION RATE CONSTANT<7 3  3 3|  0 S 0e0eA      A@  A> 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab0  VH  0޽h ? ̙33y___PPT10Y+D=' = @B +  0 (    (   ~  s *T`  V XB  0D`X  0A?`m  <T 6SIMULATION STUDY: EFFECT OF INACTIVATION RATE CONSTANT<7 3  3 3|  0 S 0e0eA      A@  A> 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab   TB  ND>?"0@NNN?N  ZF >?"6@ NNN?N 6100%H  0޽h ? ̙33y___PPT10Y+D=' = @B +D   0 k c   (   ~  s *V`  V XB  0D`X  0A?`m  < 5SIMULATION STUDY: EFFECT OF ASSOCIATION RATE CONSTANT<6 3  3 3|  0 S 0e0eA      A@  A> 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab`   TH  0޽h ? ̙33y___PPT10Y+D=' = @B +D   0 k c   (   ~  s *XV`  V XB  0D`X  0A?`m  <V 5SIMULATION STUDY: EFFECT OF ASSOCIATION RATE CONSTANT<6 3  3 3|  0 S 0e0eA      A@  A> 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab`  TH  0޽h ? ̙33y___PPT10Y+D=' = @B +G  0   z(   x  c $$V`p  V XB  0D`X  0A?`mv  <!T0Oa  \Both binding and reactivity are important for cellular potency Binding is a necessary but not sufficient precondition Reactivity is a necessary but not sufficient precondition The same target suppression can be achieved in two different ways: 1. Have a highly  sticky molecule, no matter how reactive (could be very un-reactive but if it really  sticks , it will do the job) 2. Have a highly reactive molecule, but it must be at least a little  sticky (if the molecule does not  stick at all, it does no matter how  hot the warhead is) |/MJ VV  @`  Zpja  >?"6@ NNN?N< ,$  0 RAll these things can be better understood and fine-tuned with a tool like DynaFit.SSH  0޽h ? ̙33___PPT10+DL)D' a = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+ 0 +  0 @8  (   x  c $&a `p  a  XB  0D`X  0A?`m  ZDa  >?"6@ NNN?N0: ( Brion Murray  Pfizer Leader on the PNAS paper, and in other ways Art Wittwer  Confluence Technologies (formerly Pfizer) PK/PD initial scripts (and many other ideas) Phillip Schwartz  Takeda (formerly Pfizer) Data collection for EGFR inhibitorsT+ D- 6$ b' 6u   Zda  >?"6@ NNN?N   "Questions ? http://www.biokin.com^#  H  0޽h ? ̙33y___PPT10Y+D=' = @B + 0 @ <( @Y@  X  C 4     S 49 f   >@  H  0ηo~ ? ̙33, 0 ` |(   d  c $4     3 rss49 f    H  0ηo~ ? ̙33 0 T T(  T d T c $4    T s *H#49 f   >@  H T 0ηo~ ? ̙33 0 d T(  d d d c $4    d s * 49 f   >@  H d 0ηo~ ? ̙33,x \gOPB[V4AQTM[W+ʫ4+Լ~iUZby;\ݙuWW~y<309{mgQN6*-SSJMDJJcmeee$CR~%HJu'- cPd*݆J*AQ}$HCRI5$Ց<$I $5B6:H">H^@I#$4A)IH‘D D Is$-D IHCҞbrRGTvBI$]tC"tGIO$ Mc 鋤H C<`$C"dW Gdx$##!($$!{X$H!IAȟuA[۸UG{pE?sD5/wο|s  is\ا˄I1qPVqvӢe*Xot\VҫXN8½Yuj*B$M64cm S}ъڡ=h͋ڲݚT>=GoPdUM ڂ:5@W(&@/1ܷ'$6n|IA|QSnew^Z1N +i%LΪ _V'eqz{qգ/?蕣t4h+f7 :fDkhߧ]{9Nr3۶bH} 7K{Ur۟ՍKl қ{V#);k'6~}S*72Yc; f7jOS,G <̋p=G'Z:1fﻝ+lk-;yO(7 cpЏd54lvT=]RcA5gS+=eAx}XtO彵.\j'׿r˿1\{UV#g@7L-gg6ΟW0bIwW>?[ߎ3;͊6_7-Zɭ7cwUe}}Wu? ~aA:=k^M{4s /e߭>˝nݷ0Y.)լ~;=G=BҊ^Ѭ?zMa +~8Нnݣ{^Ţ3Ӹ z^]UUL}o;וp_G紊Wpg&tWn{kw?}|=A3pn.sQ݆C˽G\s;=GOKu׹Qsj[6t]ai/ l劲= ?-:#n8~y{o^ý7ݚ2U=,ٍt?2^P_͟ަ_q[=GOK;퓪SdW?ٲ wNJs厮S '=w[nyΦ|~P=?Yޫm9o;w]Xܕ_1V\+˵7sCÞ^VH yҕU=(>ōF?<]PȵwD~W蛿q}p&ŢW~)5r27$~h7^7{u/'e7K.}U@Ϲ_OjnLuu?nd; wTlyԙY36A7Ķvs_HO|WqM>mOSexCrg=AS`z*͢L{BށMpMbqh{-g1U39/jL_Ypw9ZO0[#.s}6䎇ep۶W.%|klvdKUu8}JƆuosCNni1WI9U&mN?zV'qGx=N_x9` |Ŝi㛋]JUDžs_Ss]D/xKZ~]io0ύX9l,gza]M5 Ϟms9S|{m7\kxkJ#oY} =/^j8Y7B^Y7y3:zTϋ;}cgob˨?Ͻ|qR}w>AcY(ٻ5ce- +[ɝ?WSU?;.^}N7zt=?廨})Qum;s;0[ř&{+s׳;W|^Y_Ou:;]=|pݬp& սSХ檵Ӎݣ{tfL[76]]F=G[}Mmwѣ{t:o`>;16)JEe*PMQpTF2ğ>zG1?BC^ѝfKP%L2^ ${\:_WR0H Iq@%uBN͢(Bb-]`>1-vBzbhl\ĤiɩG$NH;jBBBJHI !fĎLHLDLbjJ:FCbSo5c3B(2je ɖPG>իe lɖ2 SRJTKP#aFGm f弑'Ls:ۚwl"#FRɗ, cHN LJƭ80,ÚO1=̏ Dʄ=XRG(Ѧ?K$솳-G=uJex)>/)A _>%/|u1eoQo _D)Hv( ~cC夫ReChRd[z+ AQ˖Fv=~liB%L% `L?ʪ.f۟/}EOʎ?/9rɝ8Ni\pQ/>~`dK[KUh|(Ɩlَ-۳e%8SDㄳӗ驖S=U9x˄3cu0(su?cE$(qt&!kp_)F"cF4Z24(خ19D-39Fu /0x FWY]J'>彜**'> j'>5NsoU㣛Z .8;ޕҟͫټ_-2h UST()˅˘sdn$ko*-˖,׊m/[6lVƜt6<.#{ԭ ^wL^S[,5l~S3-XrP_+˟c dK JJezjZn_,=Hb }F1 bP)@3oO)2(Q 1b w@7AS)gcq)cl {ǖ#2-G]IcBRϋKșJ9]Bק)H4uG˕rvNIǯ\8KV -x4JaT|!rd6[jϭ֣wnn\?˹UϝrV >2~  O{rooOs1>RlzE%~6F\ve*rf,2-DZe_%gRJ{),g*QQuX.*:˽ KF‹Yem'ʙMF6~$e2alWwO6Amv%X)?tI%fOs!A!w+93a%gLcٟmk{@Vײ 0؉"gnH Dg?x7 ) D`nJ="z D7jʹ107x D$幀{f{{? 0/t1~n Zo p7p$?Ʒ Uu/(g /yr7K5u<O"D"buKE`_MkzʞD[Q"'w7Ov1' ~쫪RơfolGq{#xYiH]K :f{)kuy>?2Wo^l~.c\JxT{WMejwP_ؤРC>mMqͥ*\x 3TZ6eSZmp̦l*eTX^ALU/ۯ*?(aLPCAd p0[EbU$$n"!N"MU,׫H4e"DbU$n"!-'$QuK^˂DD"D?+Q%/WA LdP D0Ag%}Pt."wy9A!9V/҆ J$ȿwΊ,'gVM$h)3Q##(+śF Hdؤ^{$z੝YL=s[iQk:-Qm(j@ 8Ȇ5{yURStRc-ڊ[5* J%n$vt0H:$ bc`8`$&  /uيQ>@^h^EISj2G'Eut >2gH>6gEL /DZ>466%Ri>S''(@C->c弞^¬MAa 5wGȴ3&j&oGNhݷUmK]Yyxk V-}Ϲ=hԜrߞM{sŶpl5?VPO-MO7ROF[5]n/q4lS:>!0v- 鍒 ilvY%,7JH.f? 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*Times New RomanVerdanaArial Courier NewDefault DesignSigmaPlot 11.0 GraphSlide 1"EGFR inhibition by covalent drugs6Example data: Neratinib vs. EGFR T790M / L858R mutant5Conventional kinetic analysis of covalent inhibition>Generalized numerical kinetic analysis of covalent inhibition5EGFR inhibition by covalent drugs: Mechanistic model+EGFR inhibition by covalent drugs: Results!Chemical reactivity distribution5Small number of warhead structures in the test panel3Warhead structure type vs. inactivation reactivity*Biochemical vs. cellular potency: Summary5Cellular potency: Importance of non-covalent binding+EGFR inhibition by covalent drugs: Summary Slide 14/A deeper look at enzyme-inhibitor interactionsConfidence interval method'Results: Lower limits for kon and koff!Biochemical vs. cellular potency2Biochemical vs. cellular potency: Revised summary Slide 20Possible cellular mechanism0Possible cellular mechanism in DynaFit software8Possible cellular mechanism in DynaFit software (cont.)8Possible cellular mechanism in DynaFit software (cont.)8Possible cellular mechanism in DynaFit software (cont.)7DynaFit simulation output: Afatinib strong inhibitor7DynaFit simulation output: Compound 4 weak inhibitor?DynaFit simulation output: Compound 3 intermediate inhibitorADynaFit simulation output: Like compound 3 zero inactivationADynaFit simulation output: Like compound 3 high inactivation,Like compound 3: kinact vs. free [target],Like compound 3: kinact vs. free [target])Like compound 3: kon vs. free [target])Like compound 3: kon vs. free [target]-PK / PK simulations: Summary and conclusionsAcknowledgments  Fonts UsedDesign TemplateEmbedded OLE Servers Slide Titles$_,0..  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      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