KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.

No abstract

No abstract

observed in the resulting product mixture were [PtC12(dmpe)], cis-[PtC12(PPh3)2], and [Pt(dmpe)2]C12. No evidence for the cationic complex [PtCl(PPh,)(dmpe)]+ was obtained.Reaction of [PH)12(dmpe)l with PMePb2. (a) [PtCMdmpe)] (0.037 g, 0.088 mmol) was mixed with CDCI, in a 5-mm NMR tube. After the tube had been flushed with argon, PMePh, (16.3 pL, 0.088 mmol) was added. 3'P(1HJ NMR analysis of the resulting mixture indicated that the predominant platinum-containing species was [PtC1(PMePhz)(dmpe)]C1.(b) When [PtCl,(dmpe)] (0.032 g, 0.077 mmol) was reacted with PMePh, (28.8 pL, 0.16 mmol) in CDC13 in the same way as above, the 31P(1HJ NMR spectrum indicated that the predominant platinum-con- Inorg. Chem. 1987, 26, 1524-1528 taining species in solution was [PtCI(PMePh,),]Cl. Dimethyl sulfoxide, Me2S0, is commonly used to dissolve cis-and trans-diamminedichloroplatinum(II), cis-and trans-DDP, prior to use in experiments comparing their biological activities. The solvolysis reactions of cis-and trans-DDP in Me2S0 have been investigated in this study. Me2S0 substitutes for a single chloride ligand in both cases to form c~s-[P~(NH,)~(MQSO)CI]CI (1-Cl) and tr~ns-[Pt(NH~)~(Me~S0)Cl]Cl (2-Cl). The half-lives of the cis and trans isomers in Me2S0 at 37 OC are 60 and 8 min, respectively, as determined by both optical and Is5Pt NMR spectroscopy. Kinetic studies gave activation parameters for cis-DDP solvolysis of AH* = 18.9 (1) kcal mol-' and AS* = -14.5 (2) eu (optical spectroscopy) and AH' = 19.8 (3) kcal mol-' and AS* = -1 1.6 (3) eu (IssPt NMR spectroscopy). Activation parameters for solvolysis of trans-DDP were AH' = 15.5 (1) kcal mol-' and AS* = -21.4 (2) eu (optical spectroscopy) and @ = 16.9 (3) kcal mol-' and AS* = -17.7 (4) eu (Is5Pt NMR spectroscopy). The mixed perchlorate/chloride salt of 2, trans-[Pt(NH3)2(Me2SO)Cl](C104)o,8Clo,z, has been crystallized and its structure determined by single-crystal X-ray diffraction methods. The compound crystallizes in the orthorhombic space group Pnma with a = 10.554 (3) A, b = 7.446 (1) A, c = 14.161 (2) A, V = 11 11.79 A), and Z = 4. The final RI value was 0.0395 for 799 observed reflections. The geometry of platinum is square planar, with Pt-S, Pt-N, and Pt-Cl distances of 2.204 (4), 2.1 1 (2) and 2.03

No abstract

No abstract

No abstract