1. The document provides information on several PROTAC drug candidates, including their structures, targets, developing companies, and preclinical data. 2. ARV-110 is an androgen receptor-targeting PROTAC being developed by Arvinas and Pfizer. It has a molecular weight of 812.30. 3. ARV-471 targets the estrogen receptor and is being developed by Arvinas and Pfizer. It has a molecular weight of 723.92.

1. Rubik’s
Chemistry
PROTACs in Clinic
Part 1
(Aug 2022)
Rubik’s Chemistry
Email: rubikschemistry@gmail.com (Paypal)

2. RubiksChem 2
Checklist
1
ARV-110
Bavdegalutamide
Androgen Receptor Anticancer
2 ARV-471 Estrogen Receptor Anticancer
3 CT8634 BRD9 Anticancer

3. RubiksChem
ARV-110
Structure Basic Facts PK/PD (human)
Target Androgen Receptor Dosage
Indication Anticancer Cmax
Company Arvinas AUC0-24h
Tmax
Vd
References Physical Properties fbound
1. WO2021231174
2. US20180099940
3. WO2022087125
MW 812.30 F (%)
h_pKa T1/2
h_logP (calc) CL
h_logD7.4 (calc) Metabolism
HBD Excretion
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl MW: 812.30
3

4. RubiksChem
Name ARV-110 Target Androgen Receptor Company Arvinas & Pfizer
4
SAR Statistics
compound # 528
MW range 619.7-1134.7
TPSA range 111-269
h_logP 3.44-8.77
h_logD 0.12-8.04
h_pKa 8.3-14.0
Similarity Map Analysis (UNITY fingerprint, 90% Tanimoto similarities)
2 concentrated clusters A and B, and 1 scattered cluster C (contain
candidate).
A
B
C
H
N
O
O
NC
Cl
Linker
E3 ligand
R
A
Z
X
Y
H
N
O
O
NC
Cl
Linker
E3
ligand
X, Y, Z = CH, N
B
X
Y
H
N
O
O
NC
Cl
Linker
E3
ligand
X, Y = CH, N N N
∗
∗
C

5. RubiksChem
Name ARV-110 Target Androgen Receptor Company Arvinas & Pfizer
Most populated fragments
R
i
g
i
d
i
t
y
R
i
g
i
d
i
t
y
5
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl Molecular Weight: 812.30
H
N
O
O
NC
R
H
N
O
O
NC
R
R = Cl, Me
N
N
N
N
F 1-2
N
N
N
N
O
O
NH
O
O
*N
N
O
O
NH
O
O
*O
R2
R1
R2
R1
R3
R1, R2, R3
= F, Cl, OMe
N
∗ ∗
N ∗
∗
N
N
∗
∗
N
∗
∗
N N
∗ ∗
N N
N
N
N N
N
N N N
N
N
∗ ∗
∗
∗
∗ ∗
∗
∗
∗
∗
∗
∗
N
∗
O
N
∗
N
∗
O
HN
N
∗
O
HN
N
∗ ∗
N N
∗ ∗ N
N
∗
∗
N
∗ ∗
N
∗ NH
HN O ∗
N N
∗ ∗
∗
∗
2-8
O
2-3
N N
∗ ∗
N N
∗ ∗
N ∗
N
N
O
∗ ∗
N
N
∗ ∗
O
N
∗
N O
∗
∗
∗
∗

6. RubiksChem
Name ARV-110 Target Androgen Receptor Company Arvinas & Pfizer
6
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl Molecular Weight: 812.30
N
N
N
N
H
N
O
O
NC
Cl
N
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
N
N
O
O
NH
O
O
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
N
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
F
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
F
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
Me
N
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
F
N
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
F
N
F
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Me
N
F
N
O
O
NH
O
O
N
N
N
H
N
O
O
NC
Cl
N
N
N
O
O
NH
O
O
N
N
N
N
H
N
O
O
NC
Cl
O
N
N
O
O
NH
O
O
N
N
N
H
N
O
O
NC
Cl
N

7. RubiksChem
Name ARV-110 Target Androgen Receptor Company Arvinas & Pfizer
7
N
N
N
O
OH
HO
Cl
NC
Cl
NH
HO
NH
O
NC
Cl
NH2
O
NC
Cl
•HCl
Cl
N N
O
HO
N
N
H
N
O
O
NC
Cl
Cl
HN
OH
N
N
N
H
N
O
O
NC
Cl
O
H
N
N
N
H
N
O
O
NC
Cl
O
N
F
N
O
O
NH
O
HN
•HCl
ARV-110
Cl
NC
F
or
Boc
Boc
NaH
DMF, 0 °C
58%
HCl
MeOH, rt
88%
HATU, DIPEA
DMF, rt
56%
Dess-Martin
DCM, rt
56%
NaBH(OAc)3
DCM, rt
47%
1st Generation: Gram scale
2nd Generation: Kilogram scale
Note 1: H2O content by 0.17 wt% KF titration.
DIPEA,
DMA, 90 °C
iPrOAc
crystallization
79.7%
NaClO, TEMPO(cat)
NaHCO3, NaBr
DCM/ H2O, 0 °C
ACN/H2O crystallization
90.6%
NaBH(OAc)3
Et3N, DMA, 0 - 5 °C
EtOH/H2O crystallization
EtOH 2nd crystallization
87%
NaH
DMF, -10 °C
H2O crystalliation
95%
AcCl
MeOH, rt
MBTE crystallization
95%
T3P, Et3N, EtOAc, 15 -25 °C;
1N HCl quench crystallization
79% Note 1
Repurify: DMAc/IPAc
crsystallization
85%

8. RubiksChem
Name ARV-110 Target Androgen Receptor Company Arvinas & Pfizer
8
F
F
OH
O
OH
O
N
H
O
O
NH2 F
F
N
O
O
NH
O
O
+
N
F
N
O
O
NH
O
O
N
NH
Boc
N
Boc
N
F
N
O
O
NH
O
O
HN
ONa
O
Acetic acid (5 V)
120 °C
H2O Crystallization
88%
NaHCO3
NMP, 90 °C
then water/ACN
crystallization
100%
HCl
MeOH
DCM
filtration;
IPA crystallization
85%
•HCl
OH
HO
O
O
O N
N
HO
O
OH
N
N
HO
O
OH
N
N
MeO
O
OH
N
N
MeO
O
Cl
POCl3 N
N
MeO
O
N
OH
N
N
HO
O
N
OH
hydrazine
EtOH
Br2
Acetic acid
MeOH
HCl
HN
OH NaOH
LiOH

9. RubiksChem
ARV-471
Structure Basic Facts PK/PD (human)
2229711-68-4 Target estrogen receptor Dosage
Indication Anticancer Cmax
Company Arvinas & Pfizer AUC0-24h
Tmax
Vd
References Physical Properties fbound
1. WO2022056368
2. WO2022132652
3. WO2018102725
MW 723.92 F (%)
h_pKa T1/2
h_logP (calc) CL
h_logD7.4 (calc) Metabolism
HBD Excretion
HO
H
H
N
N
N
N
O
NH
O
O
H
MW: 723.92
9

10. RubiksChem
Name ARV-471 Target estrogen receptor Company Arvinas & Pfizer
10
SAR Statistics
compound # 546
MW range 645.7-1023.2
TPSA range
h_logP
h_logD
h_pKa
Similarity Map Analysis (UNITY fingerprint, %95 Tanimoto similarities)
Contains a concentrated cluster B, and several diluted clusters.
A
B
C
HO
H
H
linker
N
O
NH
O
O
H
5
5-position linked
Lenalinomide
its enantiomer;
few other scaffolds

11. RubiksChem
Name ARV-471 Target estrogen Receptor Company Arvinas & Pfizer
Most populated fragments
11
HO
H
H
linker
N
O
NH
O
O
H
Handle1 Handle2
HO
H
H
HO
H
H
∗
∗
N
HO
X
X
X ∗
(H)Me
X = N, CH
N
∗
O
HN
NH
H
N
∗
NH
N
N
N
O
N
N
O
∗ ∗
∗ ∗ ∗
N
N
N
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
0-6
N
N
∗
∗
∗
∗
O
2
∗ ∗
N ∗
∗
N
O
∗
∗
N N N N
N N
O
∗
O
∗
N OH
HN
N
N
H
O
OH
R
∗ ∗ ∗ ∗
∗
∗
∗
∗ ∗ ∗
∗
∗
∗
∗ ∗
∗
∗
∗
∗
N N
∗ N
∗ O
H
N
∗
CH2
N
HN
N
HO
N
F N
N N
N
N O
N
N
O
N N
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗
∗ ∗
∗
∗
N
O
NH
O
O
H
∗
N
N
O
NH
O
O
H
∗
N
N
O
NH
O
O
H
∗
N
N
N
O
NH
O
O
H
∗
N
N
N
O
NH
O
O
H
∗
VHL

12. RubiksChem
Name ARV-471 Target estrogen receptor Company Arvinas & Pfizer
12
WO2022132652
HO
O
tBuO
O
O
NH
Cl
Cl
Cl
PPTS
DCM, 10 °C
31%
tBuO
OTf
N
Tf
Tf
LDA
THF, -70 °C
then 20 °C
78%
tBuO
HO B
OH
OH
Pd(dppf)Cl2
K2CO3
,
dioxane/H2O
100 °C, 88%
(90%)
OH
tBuO
OH
Br
NBS
MeCN
80%
(91%)
tBuO
OH
B
OH
OH
Pd(dppf)Cl2
K2CO3
,
dioxane/H2O
100 °C, 95%
(93%) tBuO
OH
H2
(1atm)
Pd/C (10%)
THF/MeOH(4:1)
91%
(91%)
tBuO
OH
HPLC
Column:AD
97% (92%)
tBuO
ONf
CF3(CF2)3SO2F
(NfF)
K2CO3
THF/MeCN (1:1)
91%
tBuO
N
OMe
OMe
HN
OMe
OMe
t-BuONa, Pd(OAc)2
XPhos
toluene, 90 °C
87%
tBuO
N
O
H
H2SO4
(2M)
THF, 70 °C
99%
N
O
NH
O
O
N
HN
•HCl
NaOAc, NaBH3CN
MeOH/DCM, 20 °C
51%
ARV - 471

13. RubiksChem
Name ARV-471 Target estrogen receptor Company Arvinas & Pfizer
13
OH
O
CbzHN
OtBu
O
NH2
O
CbzHN
OtBu
O
pyridine
Boc2O
NH3HCO3
dioxane
0 - 25 °C
94%
NH2
O
H2N
OtBu
O
Pd/C
H2
(50 psi)
MeOH
96%
N
BocN
OMe
O
Br
N
BocN
N
O
NH2
O
OtBu
O
DIPEA, MeCN
80 °C
81%
(92%)
HN
N
N
O
NH
O
O
•PhSO2OH
PhSO2OH
MeCN,
85 °C,
crude
US 2018 0155322
O
F
O
O
N
F
O
O
NH
H2N
O
O
NH
O
O
HN N Boc
N
N
O
O
NH
O
O
N
Boc
N
N
O
O
NH
O
O
HN
NaOAc
AcOH
DIPEA, NMP
microwave
HCl
dioxane
O
Br
O
HN N Boc
Pd2(dba)3
Xantphos
K3PO4, dioxane
O
N
O
N
Boc
N
N
Boc
OH
O
OH
N
N
Boc
OMe
O
OH
N
N
Boc
OMe
O
Br
N
N
Boc
N
O
NH
O
O
N
HN
N
O
NH
O
O
NaOH
MeOH, THF
H2O
TMSCHN2
MeOH
EtOAc
PPh3, CBr4
THF
NH
H2N
O
O
DIPEA
MeCN
HCl,
dioxane

14. RubiksChem
CFT8634
Structure Basic Facts PK/PD (human)
Target BRD9 Dosage
Indication Anticancer Cmax
Company C4 AUC0-24h
Tmax
Vd
References Physical Properties fbound
1. WO2021178920
MW 710.79 F (%)
h_pKa T1/2
h_logP (calc) CL
h_logD7.4 (calc) Metabolism
HBD Excretion
OMe
OMe
N
N
F
F
N
O
H
N
NH
O
O
F
N
MW: 710.79
2704617-96-7
CFT8634 (C4)
(S)
(S)
14

15. RubiksChem
Name CFT8634 Target BRD9 Company C4
15
SAR Statistics
compound # 321
MW range 614.70-857.29
TPSA range
h_logP
h_logD
h_pKa
Similarity Map Analysis (UNITY fingerprint, %90 Tanimoto similarities)
Contains three concentrated clusters
A
B
C
N
HN N
O
R3
R1
R2
N
O
R3
R1
R2
N
O
R3
R1
R2
X
X = CH, N
pyrazolo pyrimidone
(A, n = 133)
pyrimidone
(B, n = 73)
benzo(pyrido) pyrimidone
(C, n = 105)

16. RubiksChem
Name CFT8634 Target BRD9 Company C4
Most populated fragments
16
N
HN N
O
N
O
N
O
N
O
N
X
Y
X,Y = H, F,
OMe, CF3
OCF3, Cl, CHF2
N
N
OMe
OMe
N
N
F
F
N
O
H
N
NH
O
O
F
N
(S)
(S)
H
N
NH
O
O
F
N
H
N
NH
O
O
H
N
NH
O
O
N
H
N
NH
O
O
N
N
O
N
F
F
N
F
N
N
Y
N
N
X
X = H,F
N
N
N
X
X N
N
N
O
N
OH
N
H
N
N
N
N
N
H
N
N
N
N
N
HN
N
N
H
O
N
O
O
O
O
N
N
N
N
F
F
H
N
O
O
N

17. RubiksChem
Name CFT8634 Target BRD9 Company C4
17
OMe
OMe
N
N
F
F
N
O
H
N
NH
O
O
F
N
(S)
(S)
OMe
OMe
N
N
F
F
N
O
H
N
NH
O
O
F
N
HPLC
(S)
HN
N
F
F
H
N
NH
O
O
F
N
OMe
OMe
N
O
O
AcOH, NaOAc
MeOH/DCE, MA, 80 °C
then Si-BH3CN, rt
32%
F F
NO2
N F
NO2
N
Boc
NH
N
Boc
N F
NO2
HN
N F
NO2
N
N
Boc O
F
F
AcOH, NaOAc
MeCN, toluene;
then
toluene, 135 °C
N
F
F
Boc
AcOH,
MeOH/DCE
N
N
F
F
H
N
NH
O
O
F
N
Boc
HCl
N
N
F
F
NH2
F
N
Boc
NH
O
O
Br
NaHCO3
DMF, 85%
70%
dioxane
88%
N
N
F
F
NO2
F
N
Boc
H2
Pd/H2O
EtOAC
83%
N
N
F
F
NO2
F
N
Boc
Resolution
(+)
then
NaBH3CN
85%
•HCl
HCl
dioxane
89%
Cs2CO3
DMF, rt
92%