Advanced Estrogen Receptor Therapy for Cancer

Introduction

This innovative technology provides a targeted solution to address estrogen receptor-driven cancers by regulating estrogen receptor proteolysis. By focusing on estrogen receptor modulation, this technology supports the reduction of hormone-driven cancer growth, delivering a precision approach that offers efficacy with reduced side effects. For companies in biotechnology, oncology, and women’s health, this technology opens pathways to develop next-generation therapies for estrogen receptor-positive cancers, such as breast and ovarian cancer, meeting a critical need for safer, more effective treatments in the field of hormone-driven oncology.

The Challenge: Managing Estrogen Pathways in Cancer Treatment

Hormone-driven cancers are particularly challenging to treat, as they rely on the body’s own hormonal pathways to fuel tumor growth. Estrogen receptors in particular play a significant role in many types of cancers, such as breast cancer, where an overabundance of estrogen receptors can drive aggressive tumor growth. Traditional therapies attempt to block or reduce estrogen effects systemically, but these methods often lead to significant side effects and compromise the body’s natural hormonal balance. Patients need targeted therapies that specifically impact the cancer cells’ reliance on estrogen without impacting healthy tissue function.

Targeted Proteolysis of Estrogen Receptors

This advanced modulation technology offers a precise approach to reduce estrogen receptor activity in targeted cells by initiating receptor proteolysis, a natural process where specific proteins are broken down to reduce their activity. This selective degradation of estrogen receptors allows for a more controlled approach in disrupting cancer cell growth without the need for broad systemic hormone manipulation. By specifically targeting estrogen receptors in cancer cells, this approach minimizes off-target effects, preserving overall hormonal balance and reducing patient discomfort during treatment.

Key Benefits for Oncology and Hormone Therapy Fields

For pharmaceutical and biotechnology companies, this targeted estrogen receptor modulation technology represents a breakthrough approach to managing hormone-driven cancers. It provides a safer, more patient-centered alternative to conventional hormone therapies, addressing the urgent need for therapies that effectively inhibit tumor growth while minimizing side effects. Oncology centers, women’s health providers, and pharmaceutical developers can leverage this technology to provide patients with a more refined, reliable cancer treatment option. This technology meets the demand for specialized, precision treatments, positioning your company as a leader in advancing cancer care.

Invest in Targeted Cancer Treatment Innovation

Licensing this estrogen receptor modulation technology positions your company at the forefront of hormone-driven cancer therapy. By providing a targeted, effective solution to combat hormone-related cancers, your business can bring hope to patients and families affected by estrogen-driven tumors. This technology is a valuable asset for companies dedicated to advancing oncology, hormone therapy, and women’s health, offering an innovative path forward in the battle against cancer.

Please see terms and conditions
The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

What is claimed is:

1. A bifunctional compound having the chemical structure:


CLM-L-PTM,
or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof
wherein:

the PTM has a structure selected from the group PTM-I and PTM-II:
Figure US10604506-20200331-C00906
the CLM has a chemical structure selected from:
Figure US10604506-20200331-C00907
the L is a chemical linking group represented by -(AL)q– that is covalently bound to the ULM and the PTM, wherein AL is a chemical linker moiety and q is an integer from 1 to 100;
XPTM is O or C═O;
each of XPTM1 and XPTM2 is independently selected from N or CH;
RPTM1 is independently selected from OH, O(CO)RPTM, O-lower alkyl, wherein RPTM is an alkyl or aryl group in the ester;
RPTM2 and RPTM4 are independently selected from H, OH, halogen, CN, CF3, SO2-alkyl, O-lower alkyl;
RPTM3 and RPTM5 are independently selected from H, halogen; and
PTM-I has: at least one RPTM2 on the ring; and at least one RPTM3 on the ring;
W is selected from the group consisting of CH2, CHR, C═O, SO2, NH, and N-alkyl;
each X is independently selected from the group consisting of O, S, and CH2;
Y is selected from the group consisting of CH2, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
Z is selected from the group consisting of O, S, and CH2;
G and G′ are independently selected from the group consisting of H, linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH2-heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q1, Q2, Q3, and Q4 represent a carbon C or N substituted with a group independently selected from H and R;
A is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
n is an integer from 1-10:
R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO2R′, —SO2NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF3, —CN, —NR′SO2NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO2)NR′R″, —SO2NR′COR″, —NO2, —CO2R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3, wherein an R is modified to be covalently joined to the chemical linker group (L) or to the PTM;
R′ and R″ are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally substituted; and

Figure US10604506-20200331-P00004

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

2. The bifunctional compound of claim 1, wherein the O-lower alkyl is an alkyl chain with carbon number 1 to 3.
3. The bifunctional compound of claim 1, wherein:

each AL is independently selected from the group consisting of CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1═CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C3-11heteocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, and heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups, where RL1 or RL2, each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 RL5 groups; and
RL1, RL2, RL3, RL4 and RL5 are, each independently, H, halo, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2, CC—C1-8alkyl, CCH, CH—CH(C1-8alkyl), C(C1-8alkyl)=CH(C1-8alkyl), C(C1-8alkyl)-C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NH SO2NH(C1-8alkyl), NH SO2N(C1-8alkyl)2, or NH SO2NH2.
4. The bifunctional compound of claim 3, wherein the linker (L) comprises a group represented by a general structure selected from the group consisting of: —N(R)—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2-, —O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2-, —O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O—; —N(R)—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O; —(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O; —(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2-; (CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)t—OCH2-;
Figure US10604506-20200331-C00908
Figure US10604506-20200331-C00909
Figure US10604506-20200331-C00910
wherein each m, n, o, p, q, and r, is independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero, there is no N—O or O—O bond, R is selected from the group H, methyl and ethyl, and X is selected from the group H and F;
Figure US10604506-20200331-C00911
Figure US10604506-20200331-C00912
Figure US10604506-20200331-C00913
Figure US10604506-20200331-C00914
Figure US10604506-20200331-C00915
Figure US10604506-20200331-C00916
Figure US10604506-20200331-C00917
Figure US10604506-20200331-C00918
Figure US10604506-20200331-C00919
Figure US10604506-20200331-C00920
Figure US10604506-20200331-C00921
Figure US10604506-20200331-C00922
Figure US10604506-20200331-C00923
5. The bifunctional compound of claim 3, wherein the linker (L) is selected from the group consisting of:
Figure US10604506-20200331-C00924
Figure US10604506-20200331-C00925
Figure US10604506-20200331-C00926
Figure US10604506-20200331-C00927
Figure US10604506-20200331-C00928
Figure US10604506-20200331-C00929
Figure US10604506-20200331-C00930
wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
6. The bifunctional compound of claim 3, wherein the linker (L) is selected from the group consisting of:
Figure US10604506-20200331-C00931
Figure US10604506-20200331-C00932
Figure US10604506-20200331-C00933
Figure US10604506-20200331-C00934
Figure US10604506-20200331-C00935
Figure US10604506-20200331-C00936
Figure US10604506-20200331-C00937
Figure US10604506-20200331-C00938
Figure US10604506-20200331-C00939
Figure US10604506-20200331-C00940
Figure US10604506-20200331-C00941
Figure US10604506-20200331-C00942
Figure US10604506-20200331-C00943
Figure US10604506-20200331-C00944
Figure US10604506-20200331-C00945
Figure US10604506-20200331-C00946
Figure US10604506-20200331-C00947
Figure US10604506-20200331-C00948
Figure US10604506-20200331-C00949
Figure US10604506-20200331-C00950
Figure US10604506-20200331-C00951
Figure US10604506-20200331-C00952
Figure US10604506-20200331-C00953
Figure US10604506-20200331-C00954
Figure US10604506-20200331-C00955
Figure US10604506-20200331-C00956
Figure US10604506-20200331-C00957
Figure US10604506-20200331-C00958
Figure US10604506-20200331-C00959
Figure US10604506-20200331-C00960
Figure US10604506-20200331-C00961
Figure US10604506-20200331-C00962
Figure US10604506-20200331-C00963
Figure US10604506-20200331-C00964
Figure US10604506-20200331-C00965
Figure US10604506-20200331-C00966
Figure US10604506-20200331-C00967
Figure US10604506-20200331-C00968
wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
7. The bifunctional compound of claim 3, wherein L is selected from:
Figure US10604506-20200331-C00969
Figure US10604506-20200331-C00970
Figure US10604506-20200331-C00971
Figure US10604506-20200331-C00972
Figure US10604506-20200331-C00973
Figure US10604506-20200331-C00974
Figure US10604506-20200331-C00975
Figure US10604506-20200331-C00976
Figure US10604506-20200331-C00977
Figure US10604506-20200331-C00978
Figure US10604506-20200331-C00979
Figure US10604506-20200331-C00980
Figure US10604506-20200331-C00981
8. The bifunctional compound of claim 3, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.
9. The bifunctional compound of claim 1, wherein the linker (L) comprises the following chemical structure:
Figure US10604506-20200331-C00982
wherein:

WL1 and WL2 are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
YL1 is each independently a bond, optionally substituted linear or branched C1-C6 alkyl, and optionally one or more C atoms are replaced with O; or optionally substituted linear or branched C1-C6 alkoxy;
n is 0-10; and
a dashed line indicates the attachment point to the PTM or ULM moieties.
10. The bifunctional compound of claim 1, wherein the linker (L) comprises the following chemical structure:
Figure US10604506-20200331-C00983
wherein:

WL1 and WL2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C1-6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with RQ, each RQ is independently a H, halo, OH, NH2, NRY1RY2, CN, CF3, hydroxyl, nitro, C≡CH, C2-6 alkenyl, C2-6 alkynyl, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, OC1-3alkyl optionally substituted by 1 or more —F, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
YL1 is each independently a bond, NRYL1, O, S, NRYL2, CRYL1RYL2, C═O, C═S, SO, SO2, optionally substituted linear or branched C1-C6alkyl, and optionally one or more C atoms are replaced with O; optionally substituted linear or branched C1-C6 alkoxy;
QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 RQ, each RQ is independently H, linear or branched C1-6 alkyl optionally substituted by 1 or more halo or a C1-6 alkoxyl, or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
RYL1, RYL2 are each independently H, OH, linear or branched C1-6 alkyl optionally substituted by 1 or more halo or a C1-6 alkoxyl, or R1, R2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0-10; and
a dashed line indicates the attachment point to the PTM or ULM moieties.
11. The bifunctional compound of claim 3, wherein the linker (L) is selected from the group consisting of:
Figure US10604506-20200331-C00984
Figure US10604506-20200331-C00985
Figure US10604506-20200331-C00986
Figure US10604506-20200331-C00987
Figure US10604506-20200331-C00988
12. The bifunctional compound of claim 1, wherein the compound is selected from the compounds of Tables 1, 3, and 5.
13. A composition comprising an effective amount of a bifunctional compound of claim 1, and a pharmaceutically acceptable carrier.
14. The composition of claim 13, wherein the composition further comprises at least one of additional bioactive agent or another bifunctional compound of claim 1.
15. The composition of claim 14, wherein the additional bioactive agent is an anti-cancer agent.
16. A method of treating a disease or disorder selected from endometriosis or a cancer associated with estrogen receptor accumulation and aggregation, in a subject in need thereof, the method comprising administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one bifunctional compound of claim 1 to the subject in need thereof, wherein the composition is effective in treating or ameliorating at least one symptom of the disease or disorder.
17. The method of claim 16, wherein the disease or disorder is cancer associated with estrogen receptor accumulation and aggregation, selected from at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, or a combination thereof.
18. The method of claim 17, wherein the cancer is breast cancer.
19. The method of claim 16, wherein the disease or disorder is endometriosis.
20. A solvate or a polymorph of the bifunctional compound of claim 1.
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Title

Modulators of estrogen receptor proteolysis and associated methods of use

Inventor(s)

Andrew P. Crew, Keith R. Hornberger, Hanqing Dong, Jing Wang, Yimin Qian, Craig M. Crews

Assignee(s)

Arvinas Operations Inc

Patent #

10604506

Patent Date

March 31, 2020

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