Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors.
The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Liping H
LH
Pettus
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Kristin L
KL
Andrews
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Shon K
SK
Booker
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Jie
J
Chen
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Victor J
VJ
Cee
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Frank
F
Chavez
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Yuping
Y
Chen
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Heather
H
Eastwood
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Nadia
N
Guerrero
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Bradley
B
Herberich
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Dean
D
Hickman
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Brian A
BA
Lanman
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Jimmy
J
Laszlo
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Matthew R
MR
Lee
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
J Russell
JR
Lipford
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Bethany
B
Mattson
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Christopher
C
Mohr
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Yen
Y
Nguyen
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Mark H
MH
Norman
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
David
D
Powers
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Anthony B
AB
Reed
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Karen
K
Rex
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Christine
C
Sastri
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Nuria
N
Tamayo
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Paul
P
Wang
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Jeffrey T
JT
Winston
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Bin
B
Wu
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Tian
T
Wu
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Ryan P
RP
Wurz
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Yang
Y
Xu
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Yihong
Y
Zhou
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Andrew S
AS
Tasker
Department of Therapeutic Discovery-Medicinal Chemistry, ‡Molecular Structure, §Pharmacokinetics and Drug Metabolism, ∥Oncology Research, ⊥Pharmaceutics, #Discovery Technologies, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Hui-Ling
HL
Wang
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D052999:Quinazolinones; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim